Substituted quinazolines as inhibitors of kras g12c

ABSTRACT

or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein R1, R2a, R3a, R3b, R4a, R4b, G1, G2, L1, L2, m1, m2, A, B, W, X, Y, Z and E are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.

BACKGROUND Technical Field

The present invention is generally directed to novel compounds andmethods for their preparation and use as therapeutic or prophylacticagents, for example for treatment of cancer.

Description of the Related Art

RAS represents a group of closely related monomeric globular proteins of189 amino acids (21 kDa molecular mass) which are associated with theplasma membrane and which bind either GDP or GTP. RAS acts as amolecular switch. When RAS contains bound GDP, it is in the resting oroff position and is “inactive”. In response to exposure of the cell tocertain growth promoting stimuli, RAS is induced to exchange its boundGDP for a GTP. With GTP bound, RAS is “switched on” and is able tointeract with and activate other proteins (its “downstream targets”).The RAS protein itself has a very low intrinsic ability to hydrolyze GTPback to GDP, thus turning itself into the off state. Switching RAS offrequires extrinsic proteins termed GTPase-activating proteins (GAPs)that interact with RAS and greatly accelerate the conversion of GTP toGDP. Any mutation in RAS which affects its ability to interact with GAPor to convert GTP back to GDP will result in a prolonged activation ofthe protein and consequently a prolonged signal to the cell telling itto continue to grow and divide. Because these signals result in cellgrowth and division, overactive RAS signaling may ultimately lead tocancer.

Structurally, RAS proteins contain a G domain which is responsible forthe enzymatic activity of RAS—the guanine nucleotide binding and thehydrolysis (GTPase reaction). It also contains a C-terminal extension,known as the CAAX box, which may be post-translationally modified and isresponsible for targeting the protein to the membrane. The G domain isapproximately 21-25 kDa in size and it contains a phosphate binding loop(P-loop). The P-loop represents the pocket where the nucleotides arebound in the protein, and this is the rigid part of the domain withconserved amino acid residues which are essential for nucleotide bindingand hydrolysis (Glycine 12, Threonine 26 and Lysine 16). The G domainalso contains the so called Switch I (residues 30-40) and Switch II(residues 60-76) regions, both of which are the dynamic parts of theprotein which are often represented as the “spring-loaded” mechanismbecause of their ability to switch between the resting and loaded state.The key interaction is the hydrogen bonds formed by Threonine-35 andglycine-60 with the γ-phosphate of GTP which maintain Switch 1 andSwitch 2 regions respectively in their active conformation. Afterhydrolysis of GTP and release of phosphate, these two relax into theinactive GDP conformation.

The most notable members of the RAS subfamily are HRAS, KRAS and NRAS,mainly for being implicated in many types of cancer. However, there aremany other members including DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; MRAS;NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A; RAP2B; RAP2C;RASD1; RASD2; RASL10A; RASL10B; RASL11A; RASL11B; RASL12; REM1; REM2;RERG; RERGL; RRAD; RRAS and RRAS2.

Mutations in any one of the three main isoforms of RAS (HRAS, NRAS, orKRAS) genes are among the most common events in human tumorigenesis.About 30% of all human tumors are found to carry some mutation in RASgenes. Remarkably, KRAS mutations are detected in 25-30% of tumors. Bycomparison, the rates of oncogenic mutation occurring in the NRAS andHRAS family members are much lower (8% and 3% respectively). The mostcommon KRAS mutations are found at residue G12 and G13 in the P-loop andat residue Q61.

G12C is a frequent mutation of KRAS gene (glycine-12 to cysteine). Thismutation had been found in about 13% of cancer occurrences, about 43% oflung cancer occurrences, and in almost 100% of MYH-associates polyposis(familial colon cancer syndrome). However targeting this gene with smallmolecules is a challenge.

Accordingly, while progress has been made in this field, there remains aneed in the art for improved compounds and methods for treatment ofcancer, for example by inhibition of KRAS, HRAS or NRAS. The presentinvention fulfills this need and provides further related advantages.

BRIEF SUMMARY

In brief, the present invention provides compounds, includingstereoisomers, pharmaceutically acceptable salts, tautomers and prodrugsthereof, which are capable of modulating G12C mutant KRAS, HRAS and/orNRAS proteins. In some instances, the compounds act as electrophileswhich are capable of forming a covalent bond with the cysteine residueat position 12 of a KRAS, HRAS or NRAS G12C mutant protein. Methods foruse of such compounds for treatment of various diseases or conditions,such as cancer, are also provided.

In one embodiment, compounds having the following structure (I) areprovided:

or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrugthereof, wherein R¹, R^(2a), R^(3a), R^(3b), R^(4a), R^(4b), G¹, G², L¹,L², m¹, m², A, B, W, X, Y, Z and E are as defined herein. Pharmaceuticalcompositions comprising one or more of the foregoing compounds ofStructure (I) and a pharmaceutically acceptable carrier are alsoprovided in various other embodiments.

In other embodiments, the present invention provides a method fortreatment of cancer, the method comprising administering an effectiveamount of a pharmaceutical composition comprising any one or more of thecompounds of structure (I) to a subject in need thereof.

Other provided methods include a method for regulating activity of aKRAS, HRAS or NRAS G12C mutant protein, the method comprising reactingthe KRAS, HRAS or NRAS G12C mutant protein with any one of the compoundsof structure (I). In other embodiments, a method for inhibitingproliferation of a cell population, the method comprising contacting thecell population with any one of the compounds of structure (I) is alsoprovided.

In other embodiments, the invention is directed to a method for treatinga disorder mediated by a KRAS, HRAS or NRAS G12C mutation in a subjectin need thereof, the method comprising:

determining if the subject has a KRAS, HRAS or NRAS G12C mutation; and

if the subject is determined to have the KRAS, HRAS or NRAS G12Cmutation, then administering to the subject a therapeutically effectiveamount of a pharmaceutical composition comprising any one or morecompounds of structure (I).

In still more embodiments, the invention is directed to a method forpreparing a labeled KRAS, HRAS or NRAS G12C mutant protein, the methodcomprising reacting the KRAS, HRAS or NRAS G12C mutant with a compoundof structure (I), to result in the labeled KRAS, HRAS or NRAS G12Cprotein.

These and other aspects of the invention will be apparent upon referenceto the following detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

In the figures, identical reference numbers identify similar elements.The sizes and relative positions of elements in the figures are notnecessarily drawn to scale and some of these elements are arbitrarilyenlarged and positioned to improve figure legibility.

Further, the particular shapes of the elements as drawn are not intendedto convey any information regarding the actual shape of the particularelements, and have been solely selected for ease of recognition in thefigures.

FIG. 1 illustrates the enzymatic activity of RAS.

FIG. 2 depicts a signal transduction pathway for RAS.

FIG. 3 shows some common oncogenes, their respective tumor type andcumulative mutation frequencies (all tumors).

DETAILED DESCRIPTION

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments of theinvention. However, one skilled in the art will understand that theinvention may be practiced without these details.

Unless the context requires otherwise, throughout the presentspecification and claims, the word “comprise” and variations thereof,such as, “comprises” and “comprising” are to be construed in an open,inclusive sense, that is as “including, but not limited to”.

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment of the present invention. Thus, the appearances of thephrases “in one embodiment” or “in an embodiment” in various placesthroughout this specification are not necessarily all referring to thesame embodiment. Furthermore, the particular features, structures, orcharacteristics may be combined in any suitable manner in one or moreembodiments.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this invention belongs. As used in the specification andclaims, the singular form “a”, “an” and “the” include plural referencesunless the context clearly dictates otherwise.

“Amidinyl” refers to a radical of the form —(C═NR_(a))NR_(b)R_(c),wherein R_(a), R_(b) and R_(c) are each independently H or C₁-C₆ alkyl.

“Amino” refers to the —NH₂ radical.

“Aminylsulfone” refers to the —S(O)₂NH₂ radical.

“Carboxy” or “carboxyl” refers to the —CO₂H radical.

“Cyano” refers to the —CN radical.

“Guanidinyl” refers to a radical of the form—NR_(d)(C═NR_(a))NR_(b)R_(c), wherein R_(a), R_(b), R_(c) and R_(d) areeach independently H or C₁-C₆ alkyl.

“Hydroxy” or “hydroxyl” refers to the —OH radical.

“Imino” refers to the ═NH substituent.

“Nitro” refers to the —NO₂ radical.

“Oxo” refers to the ═O substituent.

“Thioxo” refers to the ═S substituent.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, which is saturated orunsaturated (i.e., contains one or more double and/or triple bonds),having from one to twelve carbon atoms (C₁-C₁₂ alkyl), preferably one toeight carbon atoms (C₁-C₈ alkyl) or one to six carbon atoms (C₁-C₆alkyl), and which is attached to the rest of the molecule by a singlebond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl),n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl,2-methylhexyl, ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl,penta-1,4-dienyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and thelike. Alkyl includes alkenyls (one or more carbon-carbon double bonds)and alkynyls (one or more carbon-carbon triple bonds such as ethynyl andthe like). “Amidinylalkyl” refers to an alkyl group cromprising at leastone amidinyl substituent. “Guanidinylalkyl” refers to an alkyl groupcomprising at least one guanidinyl substituent. Unless stated otherwisespecifically in the specification, an alkyl, amidinylalkyl and/orguanidinylalkyl group is optionally substituted.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, which is saturated orunsaturated (i.e., contains one or more double and/or triple bonds), andhaving from one to twelve carbon atoms, e.g., methylene, ethylene,propylene, n-butylene, ethenylene, propenylene, n-butenylene,propynylene, n-butynylene, and the like. The alkylene chain is attachedto the rest of the molecule through a single or double bond and to theradical group through a single or double bond. The points of attachmentof the alkylene chain to the rest of the molecule and to the radicalgroup can be through one carbon or any two carbons within the chain.Unless stated otherwise specifically in the specification, an alkylenechain is optionally substituted.

“Alkylcycloalkyl” refers to a radical of the formula —R_(b)R_(d) whereR_(b) is cycloalkyl chain as defined herein and R_(d) is an alkylradical as defined above. Unless stated otherwise specifically in thespecification, a alkylcycloalkyl group is optionally substituted.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl radical as defined above containing one to twelve carbon atoms.“Amidinylalkyloxy” refers to an alkoxy group cromprising at least oneamidinyl substituent on the alkyl group. “Guanidinylalkyloxy” refers toan alkoxy group comprising at least one guanidinyl substituent on thealkyl group. “Alkylcarbonylaminylalkyloxy” refers to an alkoxy groupcromprising at least one alkylcarbonylaminyl substituent on the alkylgroup. “Heterocyclylalkyloxy” refers to an alkoxy group cromprising atleast one heterocyclyl substituent on the alkyl group.“Heteroarylalkyloxy” refers to an alkoxy group cromprising at least oneheteroaryl substituent on the alkyl group. “Aminylalkyloxy” refers to analkoxy group cromprising at least one substituent of the form—NR_(a)R_(b), where R_(a) and R_(b) are each independently H or C₁-C₆alkyl, on the alkyl group. Unless stated otherwise specifically in thespecification, an alkoxy, amidinylalkyloxy, guanidinylalkyloxy,alkylcarbonylaminyl, heterocyclylalkyloxy, heteroarlyalkyloxy and/oraminylalkyloxy group is optionally substituted.

“Alkoxyalkyl” refers to a radical of the formula —R_(b)OR_(a) whereR_(a) is an alkyl radical as defined above containing one to twelvecarbon atoms and R_(b) is an alkylene radical as defined abovecontaining one to twelve carbon atoms. Unless stated otherwisespecifically in the specification, an alkoxyalkyl group is optionallysubstituted.

“Alkoxycarbonyl” refers to a radical of the formula —C(O)OR_(a) whereR_(a) is an alkyl radical as defined above containing one to twelvecarbon atoms. Unless stated otherwise specifically in the specification,an alkoxycarbonyl group is optionally substituted.

“Aryloxy” refers to a radical of the formula —OR_(a) where R_(a) is anaryl radical as defined herein. Unless stated otherwise specifically inthe specification, an aryloxy group is optionally substituted.

“Alkylaminyl” refers to a radical of the formula —NHR_(a) or—NR_(a)R_(a) where each R_(a) is, independently, an alkyl radical asdefined above containing one to twelve carbon atoms. A “haloalkylaminyl”group is an alkylaminyl group comprising at least one halo substitutenton the alkyl group. A “hydroxylalkylaminyl” group is is an alkylaminylgroup comprising at least one hydroxyl substitutent on the alkyl group.A “amidinylalkylaminyl” group is an alkylaminyl group comprising atleast one amidinyl substitutent on the alkyl group. A“guanidinylalkylaminyl” group is an alkylaminyl group comprising atleast one guanidinyl substitutent on the alkyl group. Unless statedotherwise specifically in the specification, an alkylaminyl,haloalkylaminyl, hydroxylalkylaminyl, amidinylalkylaminyl and/orguanidinylalkylaminyl group is optionally substituted.

“Aminylalkyl” refers to an alkyl group comprising at least one aminylsubstituent (—NR_(a)R_(b) wherein R_(a) and R_(b) are each independentlyH or C₁-C₆ alkyl). The aminyl substituent can be on a tertiary,secondary or primary carbon. Unless stated otherwise specifically in thespecification, an aminylalkyl group is optionally substituted.

“Aminylalkylaminyl” refers to a radical of the formula —NR_(b) whereinR_(a) is H or C₁-C₆ alkyl and R_(b) is aminylalkyl. Unless statedotherwise specifically in the specification, an aminylalkylaminyl groupis optionally substituted.

“Aminylalkoxy” refers to a radical of the formula —OR_(a)NH₂ whereinR_(a) is alkylene. Unless stated otherwise specifically in thespecification, an aminylalkoxy group is optionally substituted.

“Alkylaminylalkoxy” refers to a radical of the formula—OR_(a)NR_(b)R_(c) wherein R_(a) is alkylene and R_(b) and R_(c) areeach independently H or C₁-C₆ alkyl, provided one of R_(b) or R_(c) isC₁-C₆ alkyl. Unless stated otherwise specifically in the specification,an alkylaminylalkoxy group is optionally substituted.

“Alkylcarbonylaminyl” refers to a radical of the formula —NH(C═O)R_(a)where R_(a) is an alkyl radical as defined above containing one totwelve carbon atoms. Unless stated otherwise specifically in thespecification, an alkylcarbonylaminyl group is optionally substituted.An alkenylcarbonylaminyl is an alkylcarbonylaminyl containing at leastone carbon-carbon double bond. An alkenylcarbonylaminyl group isoptionally substituted.

“Alkylcarbonylaminylalkoxy” refers to a radical of the formula—OR_(b)NH(C═O)R_(a) where R_(a) is an alkyl radical as defined abovecontaining one to twelve carbon atoms and R_(b) is alkyelene. Unlessstated otherwise specifically in the specification, analkylcarbonylaminylalkoxy group is optionally substituted.

“Alkylaminylalkyl” refers to an alkyl group comprising at least onealkylaminyl substituent. The alkylaminyl substituent can be on atertiary, secondary or primary carbon. Unless stated otherwisespecifically in the specification, an alkylaminylalkyl group isoptionally substituted.

“Aminylcarbonyl” refers to a radical of the formula —C(═O)NR_(a)R_(b)where R_(a) and R_(b) are each independently H or alkyl. Unless statedotherwise specifically in the specification, an aminylcarbonyl group isoptionally substituted.

“Alkylaminylcarbonyl” refers to a radical of the formula—C(═O)NR_(a)R_(b), where R_(a) and R_(b) are each independently H oralkyl, provided at least one of R_(a) or R_(b) is alkyl. Unless statedotherwise specifically in the specification, an alkylaminylcarbonylgroup is optionally substituted.

“Aminylcarbonylalkyl” refers to a radical of the formula—R_(c)C(═O)NR_(a)R_(b), where R_(a) and R_(b) are each independently Hor alkyl and R_(c) is alkylene. Unless stated otherwise specifically inthe specification, an aminylcarbonylalkyl group is optionallysubstituted.

“Aminylcarbonycycloalkylalkyl” refers to a radical of the formula—R_(c)C(═O)NR_(a)R_(b), where R_(a) and R_(b) are each independently Hor alkyl and R_(c) is cycloalkyl. Unless stated otherwise specificallyin the specification, an aminylcarbonylcycloalkyl group is optionallysubstituted.

“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen,6 to 18 carbon atoms and at least one aromatic ring. For purposes ofthis invention, the aryl radical is a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems. Aryl radicals include, but are not limited to, aryl radicalsderived from aceanthrylene, acenaphthylene, acephenanthrylene,anthracene, azulene, benzene, chrysene, fluoranthene, fluorene,as-indacene, s-indacene, indane, indene, naphthalene, phenalene,phenanthrene, pleiadene, pyrene, and triphenylene. Unless statedotherwise specifically in the specification, the term “aryl” or theprefix “ar-” (such as in “aralkyl”) is meant to include aryl radicalsthat are optionally substituted.

“Aralkyl” refers to a radical of the formula —R_(b)—R_(c) where R_(b) isan alkylene chain as defined above and R_(c) is one or more arylradicals as defined above, for example, benzyl, diphenylmethyl and thelike. Unless stated otherwise specifically in the specification, anaralkyl group is optionally substituted.

“Arylalkyloxy” refers to a radical of the formula —OR_(b)—R_(c) whereR_(b) is an alkylene chain as defined above and R_(c) is one or morearyl radicals as defined above, for example, benzyl, diphenylmethyl andthe like. Unless stated otherwise specifically in the specification, anaryllkyloxy group is optionally substituted.

“Arylalkylaminyl” refers to a radical of the formula—N(R_(a))R_(b)—R_(c) where R_(a) is H or C₁-C₆ alkyl, R_(b) is analkylene chain as defined above and R_(c) is one or more aryl radicalsas defined above, for example, benzyl, diphenylmethyl and the like.Unless stated otherwise specifically in the specification, anarylalkylaminyl group is optionally substituted.

“Carboxyalkyl” refers to a radical of the formula —R_(b)—R_(c) whereR_(b) is an alkylene chain as defined above and R_(c) is a carboxy groupas defined above. Unless stated otherwise specifically in thespecification, carboxyalkyl group is optionally substituted.

“Cyanoalkyl” refers to a radical of the formula —R_(b)—R_(c) where R_(b)is an alkylene chain as defined above and R_(d) is a cyano group asdefined above. Unless stated otherwise specifically in thespecification, a cyanoalkyl group is optionally substituted.

“Cycloalkyl” or “carbocyclic ring” refers to a stable non-aromaticmonocyclic or polycyclic hydrocarbon radical consisting solely of carbonand hydrogen atoms, which may include fused or bridged ring systems,having from three to fifteen carbon atoms, preferably having from threeto ten carbon atoms, and which is saturated or unsaturated and attachedto the rest of the molecule by a single bond. Monocyclic radicalsinclude, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example,adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl,and the like. A “cycloalkenyl” is a cycloalkyl comprising one or morecarbon-carbon double bonds within the ring. Unless otherwise statedspecifically in the specification, a cycloalkyl (or cycloalkenyl) groupis optionally substituted.

“Cyanocycloalkyl” refers to a radical of the formula —R_(b)—R_(c) whereR_(b) is cycloalkylene chain and R_(c) is a cyano group as definedabove. Unless stated otherwise specifically in the specification, acyanocycloalkyl group is optionally substituted.

“Cycloalkylaminylcarbonyl” refers to a radical of the formula—C(═O)NR_(a)R_(b), where R_(a) and R_(b) are each independently H orcycloalkyl, provided at least one of R_(a) or R_(b) is cycloalkyl.Unless stated otherwise specifically in the specification, ncycloalkylaminylcarbonyl group is optionally substituted.

“Cycloalkylalkyl” refers to a radical of the formula —R_(b)R_(d) whereR_(b) is an alkylene chain as defined above and R_(d) is a cycloalkylradical as defined above. Unless stated otherwise specifically in thespecification, a cycloalkylalkyl group is optionally substituted.

“Fused” refers to any ring structure described herein which is fused toan existing ring structure in the compounds of the invention. When thefused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atomon the existing ring structure which becomes part of the fusedheterocyclyl ring or the fused heteroaryl ring is replaced with anitrogen atom.

“Halo” or “halogen” refers to bromo, chloro, fluoro or iodo.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above, e.g.,trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl,1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and thelike. Unless stated otherwise specifically in the specification, ahaloalkyl group is optionally substituted.

“Halolkoxy” refers to a radical of the formula —OR_(a) where R_(a) is ahaloalkyl radical as defined herein containing one to twelve carbonatoms. Unless stated otherwise specifically in the specification, ahaloalkoxy group is optionally substituted.

“Heterocyclyl” or “heterocyclic ring” refers to a stable 3- to18-membered non-aromatic ring radical which consists of two to twelvecarbon atoms and from one to six heteroatoms selected from the groupconsisting of nitrogen, oxygen and sulfur. Unless stated otherwisespecifically in the specification, the heterocyclyl radical is amonocyclic, bicyclic, tricyclic or tetracyclic ring system, which mayinclude fused or bridged ring systems; and the nitrogen, carbon orsulfur atoms in the heterocyclyl radical is optionally oxidized; thenitrogen atom is optionally quaternized; and the heterocyclyl radical ispartially or fully saturated. Examples of such heterocyclyl radicalsinclude, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl,tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless statedotherwise specifically in the specification. “Heterocyclyloxy” refers toa heterocyclyl group bound to the remainder of the molecule via anoxygen bond (—O—). “Heterocyclylaminyl” refers to a heterocyclyl groupbound to the remainder of the molecule via a nitrogen bond (—NR_(a)—,where R_(a) is H or C₁-C₆ alkyl). Unless stated otherwise specificallyin the specification, a heterocyclyl, heterocyclyloxy and/orhetercyclylaminyl group is optionally substituted.

“N-heterocyclyl” refers to a heterocyclyl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heterocyclyl radical to the rest of the molecule is through anitrogen atom in the heterocyclyl radical. Unless stated otherwisespecifically in the specification, a N-heterocyclyl group is optionallysubstituted.

“Heterocyclylalkyl” refers to a radical of the formula —R_(b)R_(e) whereR_(b) is an alkylene chain as defined above and R_(e) is a heterocyclylradical as defined above, and if the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl is optionallyattached to the alkyl radical at the nitrogen atom. Unless statedotherwise specifically in the specification, a heterocyclylalkyl groupis optionally substituted.

“Heterocyclylalkyloxy” refers to a radical of the formula —OR_(b)R_(e)where R_(b) is an alkylene chain as defined above and R_(e) is aheterocyclyl radical as defined above, and if the heterocyclyl is anitrogen-containing heterocyclyl, the heterocyclyl is optionallyattached to the alkyl radical at the nitrogen atom. Unless statedotherwise specifically in the specification, a heterocyclylalkyloxygroup is optionally substituted.

“Heterocyclylalkylaminyl” refers to a radical of the formula—N(R_(c))R_(b)R_(e) where R_(b) is an alkylene chain as defined aboveand R_(e) is a heterocyclyl radical as defined above, and if theheterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl isoptionally attached to the alkyl radical at the nitrogen atom, R_(c) isH or C₁-C₆ alkyl. Unless stated otherwise specifically in thespecification, a heterocyclylalkyloxy group is optionally substituted.

“Heteroaryl” refers to a 5- to 14-membered ring system radicalcomprising hydrogen atoms, one to thirteen carbon atoms, one to sixheteroatoms selected from the group consisting of nitrogen, oxygen andsulfur, and at least one aromatic ring. For purposes of this invention,the heteroaryl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heteroarylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized. Examples include, but are not limited to, azepinyl,acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e. thienyl). “Heteroaryloxy” refers to aheteroaryl group bound to the remainder of the molecule via an oxygenbond (—O—). “Heteroarylaminyl” refers to a heteroaryl group bound to theremainder of the molecule via a nitrogen bond (—NR_(a)—, where R_(a) isH or C₁-C₆ alkyl). Unless stated otherwise specifically in thespecification, a heteroaryl, heteroaryloxy and/or heteroarylaminyl groupis optionally substituted.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. Unless stated otherwise specifically inthe specification, an N-heteroaryl group is optionally substituted.

“Heteroarylalkyl” refers to a radical of the formula —R_(b)R_(f) whereR_(b) is an alkylene chain as defined above and R_(f) is a heteroarylradical as defined above. Unless stated otherwise specifically in thespecification, a heteroarylalkyl group is optionally substituted.

“Heteroarylalkyloxy” refers to a radical of the formula —OR_(b)R_(f)where R_(b) is an alkylene chain as defined above and R_(f) is aheteroaryl radical as defined above, and if the heteroaryl is anitrogen-containing heterocyclyl, the heterocyclyl is optionallyattached to the alkyl radical at the nitrogen atom. Unless statedotherwise specifically in the specification, a heteroarylalkyloxy groupis optionally substituted.

“Heteroarylalkylaminyl” refers to a radical of the formula—NR_(c)R_(b)R_(f) where R_(b) is an alkylene chain as defined above andR_(f) is a heteroaryl radical as defined above, and if the heteroaryl isa nitrogen-containing heterocyclyl, the heterocyclyl is optionallyattached to the alkyl radical at the nitrogen atom, and R_(c) is H orC₁-C₆ alkyl. Unless stated otherwise specifically in the specification,a heteroarylalkyloxy group is optionally substituted. “Hydroxylalkyl”refers to an alkyl group comprising at least one hydroxyl substituent.The —OH substituent may be on a primary, secondary or tertiary carbon.Unless stated otherwise specifically in the specification, ahydroxylalkyl group is optionally substituted. “Hydroxylalkylaminyl” isan alkylaminyl groups comprising at least one —OH substituent, which ison a primary, secondary or tertiary carbon. Unless stated otherwisespecifically in the specification, a hydroxylalkylaminyl group isoptionally substituted.

“Thioalkyl” refers to a radical of the formula —SR_(a) where R_(a) is analkyl radical as defined above containing one to twelve carbon atoms.Unless stated otherwise specifically in the specification, a thioalkylgroup is optionally substituted.

The term “substituted” used herein means any of the above groups (e.g.,alkyl, alkylene, alkylcycloalkyl, alkoxy, amidinylalkyloxy,guanidinylalkyloxy, alkylcarbonylaminylalkyloxy, heterocyclylalkyloxy,heteroarylalkyloxy, aminylalkyloxy, alkoxyalkyl, alkoxycarbonyl,haloalkylaminyl, hydroxylalkylaminyl, amidinylalkylaminyl,guanidinylalkylaminyl, aminylalkyl, aminylalkylaminyl, aminylalkoxy,alkylaminylalkoxy aryloxy, alkylaminyl, alkylcarbonylaminyl,alkylaminylalkyl, aminylcarbonyl, alkylaminylcarbonyl,alkylcarbonylaminylalkoxy, aminylcarbonylalkyl,aminylcarbonycycloalkylalkyl, thioalkyl, aryl, aralkyl, arylalkyloxy,arylalkylaminyl, carboxyalkyl, cyanoalkyl, cycloalkyl, cycloalkyloxy,cycloalkylaminyl, cyanocycloalkyl, cycloalkylaminylcarbonyl,cycloalkylalkyl, haloalkyl, haloalkoxy, heterocyclyl, heterocyclyloxy,heterocyclylaminyl, N-heterocyclyl, heterocyclylalkyl,heterocyclylalkyloxy, heterocyclylalkylaminyl, heteroaryl, N-heteroaryl,heteroarylalkyl, heteroarylalkyloxy, heteroarylalkylaminyl,hydroxylalkylaminyl and/or hydroxylalkyl) wherein at least one hydrogenatom is replaced by a bond to a non-hydrogen atoms such as, but notlimited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom ingroups such as hydroxyl groups, alkoxy groups, and ester groups; asulfur atom in groups such as thiol groups, thioalkyl groups, sulfonegroups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groupssuch as amines, amides, alkylamines, dialkylamines, arylamines,alkylarylamines, diarylamines, N-oxides, imides, and enamines; a siliconatom in groups such as trialkylsilyl groups, dialkylarylsilyl groups,alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatomsin various other groups. “Substituted” also means any of the abovegroups in which one or more hydrogen atoms are replaced by ahigher-order bond (e.g., a double- or triple-bond) to a heteroatom suchas oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen ingroups such as imines, oximes, hydrazones, and nitriles.

For example, “substituted” includes any of the above groups in which oneor more hydrogen atoms are replaced with —NR_(g)R_(h),—NR_(g)C(═O)R_(h), —NR_(g)C(═O)NR_(g)R_(h), —NR_(g)C(═O)OR_(h),—NR_(g)SO₂R_(h), —OC(═O)N R_(g)R_(h), —OR_(g), —SR_(g), —SOR_(g),—SO₂R_(g), —OSO₂R_(g), —SO₂OR_(g), ═NSO₂R_(g), and —SO₂NR_(g)R_(h).“Substituted also means any of the above groups in which one or morehydrogen atoms are replaced with —C(═O)R_(g), —C(═O)OR_(g),—C(═O)NR_(g)R_(h), —CH₂SO₂R_(g), —CH₂SO₂NR_(g)R_(h). In the foregoing,R_(g) and R_(h) are the same or different and independently hydrogen,alkyl, alkoxy, alkylaminyl, thioalkyl, aryl, aralkyl, cycloalkyl,cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl,heterocyclylalkyl, heteroaryl, N-heteroaryl and/or heteroarylalkyl.“Substituted” further means any of the above groups in which one or morehydrogen atoms are replaced by a bond to an aminyl, cyano, hydroxyl,imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylaminyl, thioalkyl,aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl,N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and/orheteroarylalkyl group. In addition, each of the foregoing substituentsmay also be optionally substituted with one or more of the abovesubstituents.

“Electrophile” or “electrophilic moiety” is any moiety capable ofreacting with a nucleophile (e.g., a moiety having a lone pair ofelectrons, a negative charge, a partial negative charge and/or an excessof electrons, for example a —SH group). Electrohiles typically areelectron poor or comprise atoms which are electron poor. In certainembodiments an electrohile contains a positive charge or partialpositive charge, has a resonance structure which contains a positivecharge or partial positive charge or is a moiety in which delocalizationor polarization of electrons results in one or more atom which containsa positive charge or partial positive charge. In some embodiments, theelectrophiles comprise conjugated double bonds, for example anα,β-unsaturated carbonyl or α,β-unsaturated thiocarbonyl compound.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound described herein that is sufficient toeffect the intended application including but not limited to diseasetreatment, as defined below. The therapeutically effective amount mayvary depending upon the intended treatment application (in vivo), or thesubject and disease condition being treated, e.g., the weight and age ofthe subject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art. The term also applies to a dose that willinduce a particular response in target cells, e.g. reduction of plateletadhesion and/or cell migration. The specific dose will vary depending onthe particular compounds chosen, the dosing regimen to be followed,whether it is administered in combination with other compounds, timingof administration, the tissue to which it is administered, and thephysical delivery system in which it is carried.

As used herein, “treatment” or “treating” refer to an approach forobtaining beneficial or desired results with respect to a disease,disorder or medical condition including but not limited to a therapeuticbenefit and/or a prophylactic benefit. By therapeutic benefit is meanteradication or amelioration of the underlying disorder being treated.Also, a therapeutic benefit is achieved with the eradication oramelioration of one or more of the physiological symptoms associatedwith the underlying disorder such that an improvement is observed in thesubject, notwithstanding that the subject may still be afflicted withthe underlying disorder. In certain embodiments, for prophylacticbenefit, the compositions are administered to a subject at risk ofdeveloping a particular disease, or to a subject reporting one or moreof the physiological symptoms of a disease, even though a diagnosis ofthis disease may not have been made.

A “therapeutic effect,” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit as described above. Aprophylactic effect includes delaying or eliminating the appearance of adisease or condition, delaying or eliminating the onset of symptoms of adisease or condition, slowing, halting, or reversing the progression ofa disease or condition, or any combination thereof.

The term “co-administration,” “administered in combination with,” andtheir grammatical equivalents, as used herein, encompass administrationof two or more agents to an animal, including humans, so that bothagents and/or their metabolites are present in the subject at the sametime. Co-administration includes simultaneous administration in separatecompositions, administration at different times in separatecompositions, or administration in a composition in which both agentsare present.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as, but are not limited to,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

“Pharmaceutically acceptable base addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from inorganic bases include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, deanol,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, benethamine, benzathine, ethylenediamine, glucosamine,methylglucamine, theobromine, triethanolamine, tromethamine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. Particularly preferred organic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, cholineand caffeine.

The terms “antagonist” and “inhibitor” are used interchangeably, andthey refer to a compound having the ability to inhibit a biologicalfunction of a target protein, whether by inhibiting the activity orexpression of the protein, such as KRAS, HRAS or NRAS G12C. Accordingly,the terms “antagonist” and “inhibitors” are defined in the context ofthe biological role of the target protein. While preferred antagonistsherein specifically interact with (e.g. bind to) the target, compoundsthat inhibit a biological activity of the target protein by interactingwith other members of the signal transduction pathway of which thetarget protein is a member are also specifically included within thisdefinition. A preferred biological activity inhibited by an antagonistis associated with the development, growth, or spread of a tumor.

The term “agonist” as used herein refers to a compound having theability to initiate or enhance a biological function of a targetprotein, whether by inhibiting the activity or expression of the targetprotein. Accordingly, the term “agonist” is defined in the context ofthe biological role of the target polypeptide. While preferred agonistsherein specifically interact with (e.g. bind to) the target, compoundsthat initiate or enhance a biological activity of the target polypeptideby interacting with other members of the signal transduction pathway ofwhich the target polypeptide is a member are also specifically includedwithin this definition.

As used herein, “agent” or “biologically active agent” refers to abiological, pharmaceutical, or chemical compound or other moiety.Non-limiting examples include a simple or complex organic or inorganicmolecule, a peptide, a protein, an oligonucleotide, an antibody, anantibody derivative, antibody fragment, a vitamin derivative, acarbohydrate, a toxin, or a chemotherapeutic compound. Various compoundscan be synthesized, for example, small molecules and oligomers (e.g.,oligopeptides and oligonucleotides), and synthetic organic compoundsbased on various core structures. In addition, various natural sourcescan provide compounds for screening, such as plant or animal extracts,and the like.

“Signal transduction” is a process during which stimulatory orinhibitory signals are transmitted into and within a cell to elicit anintracellular response. A modulator of a signal transduction pathwayrefers to a compound which modulates the activity of one or morecellular proteins mapped to the same specific signal transductionpathway. A modulator may augment (agonist) or suppress (antagonist) theactivity of a signaling molecule.

An “anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent”refers to any agent useful in the treatment of a neoplastic condition.One class of anti-cancer agents comprises chemotherapeutic agents.“Chemotherapy” means the administration of one or more chemotherapeuticdrugs and/or other agents to a cancer patient by various methods,including intravenous, oral, intramuscular, intraperitoneal,intravesical, subcutaneous, transdermal, buccal, or inhalation or in theform of a suppository.

The term “cell proliferation” refers to a phenomenon by which the cellnumber has changed as a result of division. This term also encompassescell growth by which the cell morphology has changed (e.g., increased insize) consistent with a proliferative signal.

The term “selective inhibition” or “selectively inhibit” refers to abiologically active agent refers to the agent's ability topreferentially reduce the target signaling activity as compared tooff-target signaling activity, via direct or indirect interaction withthe target.

“Subject” refers to an animal, such as a mammal, for example a human.The methods described herein can be useful in both human therapeuticsand veterinary applications. In some embodiments, the subject is amammal, and in some embodiments, the subject is human.

“Mammal” includes humans and both domestic animals such as laboratoryanimals and household pets (e.g., cats, dogs, swine, cattle, sheep,goats, horses, rabbits), and non-domestic animals such as wildlife andthe like.

“Radiation therapy” means exposing a subject, using routine methods andcompositions known to the practitioner, to radiation emitters such asalpha-particle emitting radionuclides (e.g., actinium and thoriumradionuclides), low linear energy transfer (LET) radiation emitters(i.e. beta emitters), conversion electron emitters (e.g. strontium-89and samarium-153-EDTMP, or high-energy radiation, including withoutlimitation x-rays, gamma rays, and neutrons.

An “anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent”refers to any agent useful in the treatment of a neoplastic condition.One class of anti-cancer agents comprises chemotherapeutic agents.“Chemotherapy” means the administration of one or more chemotherapeuticdrugs and/or other agents to a cancer patient by various methods,including intravenous, oral, intramuscular, intraperitoneal,intravesical, subcutaneous, transdermal, buccal, or inhalation or in theform of a suppository.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein (e.g., compound of structure (I)). Thus, theterm “prodrug” refers to a precursor of a biologically active compoundthat is pharmaceutically acceptable. In some aspects, a prodrug isinactive when administered to a subject, but is converted in vivo to anactive compound, for example, by hydrolysis. The prodrug compound oftenoffers advantages of solubility, tissue compatibility or delayed releasein a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs(1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugsis provided in Higuchi, T., et al., “Pro-drugs as Novel DeliverySystems,” A.C.S. Symposium Series, Vol. 14, and in BioreversibleCarriers in Drug Design, ed. Edward B. Roche, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporated infull by reference herein. The term “prodrug” is also meant to includeany covalently bonded carriers, which release the active compound invivo when such prodrug is administered to a mammalian subject. Prodrugsof an active compound, as described herein, are typically prepared bymodifying functional groups present in the active compound in such a waythat the modifications are cleaved, either in routine manipulation or invivo, to the parent active compound. Prodrugs include compounds whereina hydroxy, amino or mercapto group is bonded to any group that, when theprodrug of the active compound is administered to a mammalian subject,cleaves to form a free hydroxy, free amino or free mercapto group,respectively. Examples of prodrugs include, but are not limited to,acetate, formate and benzoate derivatives of a hydroxy functional group,or acetamide, formamide and benzamide derivatives of an amine functionalgroup in the active compound and the like.

The term “in vivo” refers to an event that takes place in a subject'sbody.

The invention disclosed herein is also meant to encompass allpharmaceutically acceptable compounds of structure (I) beingisotopically-labelled by having one or more atoms replaced by an atomhaving a different atomic mass or mass number. Examples of isotopes thatcan be incorporated into the disclosed compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, andiodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P,³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I, respectively. These radiolabelledcompounds could be useful to help determine or measure the effectivenessof the compounds, by characterizing, for example, the site or mode ofaction, or binding affinity to pharmacologically important site ofaction. Certain isotopically-labelled compounds of structure (I), forexample, those incorporating a radioactive isotope, are useful in drugand/or substrate tissue distribution studies. The radioactive isotopestritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful forthis purpose in view of their ease of incorporation and ready means ofdetection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence are preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof structure (I) can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed in the Preparations and Examples as set out below using anappropriate isotopically-labeled reagent in place of the non-labeledreagent previously employed.

The invention disclosed herein is also meant to encompass the in vivometabolic products of the disclosed compounds. Such products may resultfrom, for example, the oxidation, reduction, hydrolysis, amidation,esterification, and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising administering a compound of thisinvention to a mammal for a period of time sufficient to yield ametabolic product thereof. Such products are typically identified byadministering a radiolabelled compound of the invention in a detectabledose to an animal, such as rat, mouse, guinea pig, monkey, or to human,allowing sufficient time for metabolism to occur, and isolating itsconversion products from the urine, blood or other biological samples.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

Often crystallizations produce a solvate of the compound of theinvention. As used herein, the term “solvate” refers to an aggregatethat comprises one or more molecules of a compound of the invention withone or more molecules of solvent. In some embodiments, the solvent isewater, in which case the solvate is a hydrate. Alternatively, in otherembodiments, the solvent is an organic solvent. Thus, the compounds ofthe present invention may exist as a hydrate, including a monohydrate,dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate and thelike, as well as the corresponding solvated forms. In some aspects, thecompound of the invention is a true solvate, while in other cases, thecompound of the invention merely retains adventitious water or is amixture of water plus some adventitious solvent.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical may or may not be substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

A “pharmaceutical composition” refers to a formulation of a compound ofthe invention and a medium generally accepted in the art for thedelivery of the biologically active compound to mammals, e.g., humans.Such a medium includes all pharmaceutically acceptable carriers,diluents or excipients therefor.

“Pharmaceutically acceptable carrier, diluent or excipient” includeswithout limitation any adjuvant, carrier, excipient, glidant, sweeteningagent, diluent, preservative, dye/colorant, flavor enhancer, surfactant,wetting agent, dispersing agent, suspending agent, stabilizer, isotonicagent, solvent, or emulsifier which has been approved by the UnitedStates Food and Drug Administration as being acceptable for use inhumans or domestic animals.

The compounds of the invention, or their pharmaceutically acceptablesalts may contain one or more asymmetric centers and may thus give riseto enantiomers, diastereomers, and other stereoisomeric forms that aredefined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, for example, chromatography andfractional crystallization. Conventional techniques for thepreparation/isolation of individual enantiomers include chiral synthesisfrom a suitable optically pure precursor or resolution of the racemate(or the racemate of a salt or derivative) using, for example, chiralhigh pressure liquid chromatography (HPLC). When the compounds describedherein contain olefinic double bonds or other centres of geometricasymmetry, and unless specified otherwise, it is intended that thecompounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

The present invention includes all manner of rotamers andconformationally restricted states of a compound of the invention.Atropisomers, which are stereoisomers arising because of hinderedrotation about a single bond, where energy differences due to stericstrain or other contributors create a barrier to rotation that is highenough to allow for isolation of individual conformers, are alsoincluded. As an example, certain compounds of the invention may exist asmixtures of atropisomers or purified or enriched for the presence of oneatropisomer. Non-limiting examples of compounds which exist asatropisomers include the following compounds:

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

A “tautomer” refers to a proton shift from one atom of a molecule toanother atom of the same molecule. The present invention includestautomers of any said compounds.

The chemical naming protocol and structure diagrams used herein are amodified form of the I.U.P.A.C. nomenclature system, using the ACD/NameVersion 9.07 software program and/or ChemDraw Ultra Version 11.0.1software naming program (CambridgeSoft). For complex chemical namesemployed herein, a substituent group is typically named before the groupto which it attaches. For example, cyclopropylethyl comprises an ethylbackbone with a cyclopropyl substituent. Except as described below, allbonds are identified in the chemical structure diagrams herein, exceptfor all bonds on some carbon atoms, which are assumed to be bonded tosufficient hydrogen atoms to complete the valency.

Compounds

In an aspect, the invention provides compounds which are capable ofselectively binding to and/or modulating a G12C mutant KRAS, HRAS orNRAS protein. The compounds may modulate the G12C mutant KRAS, HRAS orNRAS protein by reaction with an amino acid. While not wishing to bebound by theory, the present applicants believe that, in someembodiments, the compounds of the invention selectively react with theG12C mutant KRAS, HRAS or NRAS proteins by forming a covalent bond withthe cysteine at the 12 position of a G12C mutant KRAS, HRAS or NRASprotein. By binding to the Cystine 12, the compounds of the inventionmay lock the switch II of the G12C mutant KRAS, HRAS or NRAS into aninactive stage. This inactive stage may be distinct from those observedfor GTP and GDP bound KRAS, HRAS or NRAS. Some compounds of theinvention may also be able to perturb the switch I conformation. Somecompounds of the invention may favor the binding of the bound KRAS, HRASor NRAS to GDP rather than GTP and therefore sequester the KRAS, HRAS orNRAS into an inactive KRAS, HRAS or NRAS GDP state. Because effectorbinding to KRAS, HRAS or NRAS is highly sensitive to the conformation ofswitch I and II, the irreversible binding of these compounds may disruptKRAS, HRAS or NRAS downstream signaling.

As noted above, in one embodiment of the present invention, compoundshaving activity as modulators of a G12C mutant KRAS, HRAS or NRASprotein are provided, the compounds have the following structure (I):

or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomerthereof, wherein:

A is CR¹, CR^(2b), NR⁷ or S;

B is a bond, CR¹ or CR^(2c)

G¹ and G² are each independently N or CH;

W, X and Y are each independently N, NR⁵ or CR⁶;

Z is a bond, N or CR⁶, or Z is NH when Y is C═O;

L¹ is a bond or NR⁷;

L² is a bond or alkylene;

R¹ is H, cyano, halo, CF₃, C₁-C₆alkyl, C₁-C₆alkylaminyl, C₃-C₈cycloalkyl, C₁-C₆alkenyl or C₃-C₈cycloalkenyl, heterocyclyl, heteroaryl,aryloxy, heteroaryloxy or aryl;

R^(2a), R^(2b) and R^(2c) are each independently H, halo, hydroxyl,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₃-C₈ cycloalkyl, heteroarylor aryl;

R^(3a) and R^(3b) are, at each occurrence, independently H, —OH, —NH₂,—CO₂H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ alkynyl, hydroxylalkly,aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl; or R^(3a) and R^(3b) join to forma carbocyclic or heterocyclic ring; or R^(3a) is H, —OH, —NH₂, —CO₂H,halo, cyano, C₁-C₆ alkyl, C₁-C₆ alkynyl, hydroxylalkly, aminylalkyl,alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl oraminylcarbonyl, and R^(3b) joins with R^(4b) to form a carbocyclic orheterocyclic ring;

R^(4a) and R^(4b) are, at each occurrence, independently H, —OH, —NH₂,—CO₂H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ alkynyl, hydroxylalkly,aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl; or R^(4a) and R^(4b) join to forma carbocyclic or heterocyclic ring; or R^(4a) is H, —OH, —NH₂, —CO₂H,halo, cyano, C₁-C₆ alkyl, C₁-C₆ alkynyl, hydroxylalkly, aminylalkyl,alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl oraminylcarbonyl, and R^(4b) joins with R^(3b) to form a carbocyclic orheterocyclic ring;

R⁵ is, at each occurrence, independently H, C₁-C₆ alkyl or a bond to L¹;

R⁶ is, at each occurrence, independently H, oxo, cyano, cyanoalkyl,amino, aminylalkyl, aminylalkylaminyl, aminylcarbonyl, aminylsulfonyl,—CO₂NR^(a)R^(b), wherein R^(a) and R^(b), are each independently H orC1-C6 alkyl or R^(a) and R^(b) join to form a carbocyclic orheterocyclic ring, alkylaminyl, haloalkylaminyl, hydroxylalkyaminyl,amindinylalkyl, amidinylalkoxy, amindinylalkylaminyl, guanidinylalkyl,guanidinylalkoxy, guanidinylalkylaminyl, C₁-C₆ alkoxy, aminylalkoxy,alkylcarbonylaminylalkoxy, C₁-C₆ alkyl, heterocyclyl, heterocyclyloxy,heterocyclylalkyloxy, heterocyclylaminyl, heterocyclylalkylaminyl,heteroaryl, heteroaryloxy, heteroarylalkyloxy, heteroarylaminyl,heteroarylalkylaminyl, aryl, aryloxy, arylaminyl, arylalkylaminyl,arylalkyloxy or a bond to L1;

R⁷ is H or C₁-C₆ alkyl;

m¹ and m² are each independently 1, 2 or 3;

indicates a single or double bond such that all valences are satisfied;and

E is an electrophilic moiety capable of forming a covalent bond with thecysteine residue at position 12 of a KRAS, HRAS or NRAS G12C mutantprotein,

wherein at least one of W, X, Y or Z is CR⁶ where R⁶ is a bond to L¹,and

provided that when R¹, R^(2a), R^(2b) and R^(2c) are all independentlyselected from H and halo, then X and Z are both N and at least one ofR^(3a), R^(3b), R^(4a) or R^(4b) is not H, and provided that at leastone of R^(2a), R^(2b) or R^(2c) is not H when R¹ is pyridyl.

In some other embodiments of compound (I):

A is CR¹, CR^(2b), NR⁷ or S;

B is a bond, CR¹ or CR^(2c)

G¹ and G² are each independently N or CH;

W, X and Y are each independently N, NR⁵ or CR⁶;

Z is a bond, N or CR^(6a) or Z is NH when Y is C═O;

L¹ is a bond or NR⁷;

L² is a bond or alkylene;

R¹ is heterocyclyl, heteroaryl or aryl;

R^(2a), R^(2b) and R^(2c) are each independently H, halo, hydroxyl,C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₃-C₈ cycloalkyl, heteroarylor aryl;

R^(3a) and R^(3b) are, at each occurrence, independently H, —OH, —NH₂,—CO₂H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ alkynyl, hydroxylalkly,aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl; or R^(3a) and R^(3b) join to forma carbocyclic or heterocyclic ring; or R^(3a) is H, —OH, —NH₂, —CO₂H,halo, cyano, C₁-C₆ alkyl, C₁-C₆ alkynyl, hydroxylalkly, aminylalkyl,alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl oraminylcarbonyl, and R^(3b) joins with R^(4b) to form a carbocyclic orheterocyclic ring;

R^(4a) and R^(4b) are, at each occurrence, independently H, —OH, —NH₂,—CO₂H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ alkynyl, hydroxylalkly,aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl; or R^(4a) and R^(4b) join to forma carbocyclic or heterocyclic ring; or R^(4a) is H, —OH, —NH₂, —CO₂H,halo, cyano, C₁-C₆ alkyl, C₁-C₆ alkynyl, hydroxylalkly, aminylalkyl,alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl oraminylcarbonyl, and R^(4b) joins with R^(3b) to form a carbocyclic orheterocyclic ring;

R⁵ is, at each occurrence, independently H, C₁-C₆ alkyl or a bond to L¹;

R⁶ is, at each occurrence, independently H, oxo, cyano, cyanoalkyl,amino, aminylalkyl, aminylalkylaminyl, aminylcarbonyl, aminylsulfonyl,—CO₂NR^(a)R^(b), wherein R^(a) and R^(b), are each independently H orC₁-C₆ alkyl or R^(a) and R^(b) join to form a carbocyclic orheterocyclic ring, alkylaminyl, haloalkylaminyl, hydroxylalkyaminyl,amindinylalkyl, amidinylalkoxy, amindinylalkylaminyl, guanidinylalkyl,guanidinylalkoxy, guanidinylalkylaminyl, C₁-C₆ alkoxy, aminylalkoxy,alkylaminylalkoxy alkylcarbonylaminylalkoxy, C₁-C₆ alkyl, heterocyclyl,heterocyclyloxy, heterocyclylalkyloxy, heterocyclylaminyl,heterocyclylalkylaminyl, heteroaryl, heteroaryloxy, heteroarylalkyloxy,heteroarylaminyl, heteroarylalkylaminyl, aryl, aryloxy, arylaminyl,arylalkylaminyl, arylalkyloxy or a bond to L¹;

R^(6a) is H, alkyl or a bond to L¹;

R⁷ is H or C₁-C₆ alkyl

m¹ and m² are each independently 1, 2 or 3;

indicates a single or double bond such that all valences are satisfied;and

E is an electrophilic moiety capable of forming a covalent bond with thecysteine residue at position 12 of a KRAS, HRAS or NRAS G12C mutantprotein,

wherein at least one of W, X, Y or Z is CR⁶ where R⁶ is a bond to L¹ orat least one of W, X or Y is NR⁵, wherein R⁵ is a bond to L¹, and

provided that least one of R^(2a), R^(2b) or R^(2c) is not H when R¹ ispyridyl.

In some of the foregoing embodiments, R¹ is aryl. In other embodiments,R¹ is heterocyclyl. In still other embodiments, R¹ is heteroaryl,provided that least one of R^(2a), R^(2b) or R^(2c) is not H when R¹ ispyridyl. In some other embodiments, C₁-C₆ haloalkyl is CF₃.

In some embodiments of the compound of structure (I), the bond between Wand X is a double bond. In other embodiments, the bond between Y and Zis a double bond. In more embodiments, the bond between A and B is adouble bond. In still more embodiments, the bonds between W and X, Y andZ and A and B are each double bonds.

In some other embodiments, Z is a bond, N or CR⁶. In some embodiments, Zis a bond, N or CR^(6a), wherein R^(6a) is H, alkyl or a bond to L¹. Inother embodiments Z is NH when Y is C═O

In some more embodiments of the foregoing compound of structure (I):

A is CR¹, CR^(2b), NR⁷ or S;

B is a bond, CR¹ or CR^(2c)

G¹ and G² are each independently N or CH;

W, X and Y are each independently N, NR⁵ or CR⁶;

Z is a bond, N or CR⁶;

L¹ is a bond or NR⁷;

L² is a bond or alkylene;

R¹ is H, cyano, halo, heterocyclyl, heteroaryl, aryloxy or aryl;

R^(2a), R^(2b) and R^(2C) are each independently H, halo, hydroxyl,C₁-C₆ alkyl, C₁-C₆ haloalkyl C₃-C₈ cycloalkyl or aryl;

R^(3a) and R^(3b) are, at each occurrence, independently H, —OH, —NH₂,—CO₂H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ alkynyl, hydroxylalkly,aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl; or R^(3a) and R^(3b) join to forma carbocyclic or heterocyclic ring; or R^(3a) is H, —OH, —NH₂, —CO₂H,halo, cyano, C₁-C₆ alkyl, C₁-C₆ alkynyl, hydroxylalkly, aminylalkyl,alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl oraminylcarbonyl, and R^(3b) joins with R^(4b) to form a carbocyclic orheterocyclic ring;

R^(4a) and R^(4b) are, at each occurrence, independently H, —OH, —NH₂,—CO₂H, halo, cyano, C₁-C₆ alkyl, C₁-C₆ alkynyl, hydroxylalkly,aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl; or R^(4a) and R^(4b) join to forma carbocyclic or heterocyclic ring; or R^(4a) is H, —OH, —NH₂, —CO₂H,halo, cyano, C₁-C₆ alkyl, C₁-C₆ alkynyl, hydroxylalkly, aminylalkyl,alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl oraminylcarbonyl, and R^(4b) joins with R^(3b) to form a carbocyclic orheterocyclic ring;

R⁵ and R⁷ are each independently H or C₁-C₆ alkyl;

R⁶ is, at each occurrence, independently H, oxo, cyano, cyanoalkyl,amino, aminylcarbonyl, alkylaminyl, C₁-C₆ alkoxy, C₁-C₆ alkyl or a bondto L¹;

m¹ and m² are each independently 1, 2 or 3;

indicates a single or double bond such that all valences are satisfied;and

E is an electrophilic moiety capable of forming a covalent bond with thecysteine residue at position 12 of a KRAS, HRAS or NRAS G12C mutantprotein,

wherein at least one of W, X, Y or Z is CR⁶ where R⁶ is a bond to L¹,and

provided that when R¹, R^(2a), R^(2b) and R^(2c) are all independentlyselected from H and halo, then X and Z are both N and at least one ofR^(3a), R^(3b), R^(4a) or R^(4b) is not H, and provided that at leastone of R^(2a), R^(2b) or R^(2c) is not H when R¹ is pyridyl.

In some other embodiments of the foregoing compound of structure (I):

A is CR^(2b), NR⁷ or S;

B is a bond or CR^(2c)

G¹ and G² are each independently N or CH;

W, X and Y are each independently N, NR⁵ or CR⁶;

Z is a bond, N or CR⁶;

L¹ is a bond or NR⁷;

L² is a bond or alkylene;

R¹ is cyano, C₁-C₆alkyl, C₁-C₆alkylaminyl, C₃-C₈ cycloalkyl,C₁-C₆alkenyl or C₃-C₈ cycloalkenyl, heterocyclyl or aryl;

R^(2a), R^(2b) and R^(2c) are each independently H, halo, C₁-C₆alkyl orC₃-C₈ cycloalkyl;

R^(3a) and R^(3b) are, at each occurrence, independently H, —OH, —NH₂,—CO₂H, halo, cyano, hydroxylalkly, aminylalkyl, cyanoalkyl, carboxyalkylor aminylcarbonyl; or R^(3a) and R^(3b) join to form a carbocyclic orheterocyclic ring; or R^(3a) is H, —OH, —NH₂, —CO₂H, halo, cyano,hydroxylalkly, aminylalkyl, cyanoalkyl, carboxyalkyl or aminylcarbonyl,and R^(3b) joins with R^(4b) to form a carbocyclic or heterocyclic ring;

R^(4a) and R^(4b) are, at each occurrence, independently H, —OH, —NH₂,—CO₂H, halo, cyano, hydroxylalkly, aminylalkyl, cyanoalkyl, carboxyalkylor aminylcarbonyl; or R^(4a) and R^(4b) join to form a carbocyclic orheterocyclic ring; or R^(4a) is H, —OH, —NH₂, —CO₂H, halo, cyano,hydroxylalkly, aminylalkyl, cyanoalkyl, carboxyalkyl or aminylcarbonyl,and R^(4b) joins with R^(3b) to form a carbocyclic or heterocyclic ring;

R⁵ and R⁷ are each independently H or C₁-C₆alkyl;

R⁶ is, at each occurrence, independently H, cyano, amino, alkylaminyl,C₁-C₆alkoxy, C₁-C₆alkyl or a bond to L¹;

m¹ and m² are each independently 1, 2 or 3;

indicates a single or double bond such that all valences are satisfied;and

E is an electrophilic moiety capable of forming a covalent bond with thecysteine residue at position 12 of a KRAS, HRAS or NRAS G12C mutantprotein,

wherein at least one of W, X or Y is CR⁶ where R⁶ is a bond to L¹.

In still other embodiments of the foregoing compound of structure (I),R¹ is H, cyano, halo, heterocyclyl, heteroaryl, aryloxy or aryl.

The structure of E is not particularly limited provided it is capable offorming a covalent bond with a nucleophile, such as the cysteine residueat position 12 of a KRAS, HRAS or NRAS G12C mutant protein. Accordingly,moieties which are capable of reaction with (e.g., by covalent bondformation) a nucleophile are preferred. In certain embodiments, E iscapable of reacting in a conjugate addition manner (e.g., 1.4-conjugateaddition) with an appropriately reactive nucleophile. In someembodiments, E comprises conjugated pi bonds such that delocalization ofelectrons results in at least one atom (e.g., a carbon atom) having apositive charge, partial positive charge or a polarized bond. In otherembodiments, E comprises one or more bonds wherein the electronegativityof the two atoms forming the bonds is sufficiently different such that apartial positive charge (e.g., by polarization of the bond) resides onone of the atoms, for example on a carbon atom. E moieties comprisingcarbon-halogen bonds, carbon-oxygen bonds or carbon bonds to variousleaving groups known in the art are examples of such E moieties.

In certain embodiments of the foregoing, E has the following structure:

wherein:

represents a double or triple bond;

Q is —C(═O)—, —C(═NR^(8′))—, —NR⁸C(═O)—, —S(═O)₂— or —NR⁸S(═O)₂—;

R⁸ is H, C₁-C₆alkyl or hydroxylalkyl;

R^(8′) is H, —OH, —CN or C₁-C₆alkyl; and

when

is a double bond then R⁹ and R¹⁰ are each independently H, cyano,carboxyl, C₁-C₆alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, orhydroxylalkyl or R⁹ and R¹⁰ join to form a carbocyclic or heterocyclicring;

when

is a triple bond; then R⁹ is absent and R¹⁰ is H, C₁-C₆alkyl,aminylalkyl, alkylaminylalkyl or hydroxylalkyl.

In certain embodiments when

is a double bond then R⁹ and R¹⁰ are each independently H, cyano,C₁-C₆alkyl, aminylalkyl, alkylaminylalkyl, or hydroxylalkyl or R⁹ andR¹⁰ join to form a carbocyclic or heterocyclic ring.

In some of the foregoing embodiments, Q is —C(═O)—, —NR⁸C(═O)—, —S(═O)₂—or —NR⁸S(═O)₂—.

In some other of the foregoing embodiments, Q is —C(═NR^(8′))—, whereinR^(8′) is H, —OH, —CN or C₁-C₆alkyl. For example, in some embodimentsR^(8′) is H. In other embodiments, R^(8′) is —CN. In other embodiments,R^(8′) is —OH.

In some embodiments, the compound has the following structure (I′):

wherein R′ is R¹ and R″ is R^(2c) or R′ is H and R″ is R¹.

In other embodiments, the compound has the following structure (I′a):

wherein:

represents a double or triple bond;

Q is —C(═O)—, —C(═NR^(8′))—, —NR⁸C(═O)—, —S(═O)₂— or —NR⁸S(═O)₂—;

R⁸ is H, C₁-C₆alkyl or hydroxylalkyl;

R^(8′) is H, —OH, —CN or C₁-C₆alkyl;

when

is a double bond then R⁹ and R¹⁰ are each independently H, cyano,carboxyl, C₁-C₆alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl,heteroaryl or hydroxylalkyl or R⁹ and R¹⁰ join to form a carbocyclic orheterocyclic ring;

when

is a triple bond then R⁹ is absent and R¹⁰ is H, C₁-C₆alkyl,aminylalkyl, alkylaminylalkyl or hydroxylalkyl; and

R′ is R¹ and R″ is R^(2c) or R′ is H and R″ is R¹.

In some of the foregoing embodiments of compound (I′a), Q is —C(═O)—,—NR⁸C(═O)—, —S(═O)₂— or —NR⁸S(═O)₂—.

In some other of the foregoing embodiments of compound (I′a), Q is—C(═NR^(8′))—, wherein R⁸ is H, —OH, —CN or C₁-C₆alkyl. For example, insome embodiments R^(8′) is H. In other embodiments, R^(8′) is —CN. Inother embodiments, R^(8′) is —OH.

In still more embodiments of the foregoing compounds, the compound hasone of the following structures (I′b), (I′c), (I′d) or (I′e):

In still more embodiments, the compound has one of the followingstructures (I′f), (I′g), (I′h) or (I′i):

In some embodiments of the compounds of structures (I′f), (I′g), (I′h)or (I′i), R¹ is aryl and R^(2c) and R^(2b) are independently selectedfrom H and halo, for example in some further embodiments R¹ is aryl andR^(2c) and R^(2b) are independently selected from halo.

In different embodiments, the compound has one of the followingstructures (I′j), (I′k), (I′l) or (I′m):

In some embodiments of the compounds of structures (I′j), (I′k), (I′l)or (I′m), R¹ is aryl and R^(2a) and R^(2b) are independently selectedfrom H and halo, for example in some further embodiments R¹ is aryl andR^(2a) and R^(2b) are independently selected from halo.

In other embodiments, the compound has the following structure (I″):

wherein R′ is R¹ and R″ is R^(2c) or R′ is H and R″ is R¹. For example,in some embodiments the compound has the following structure (I″a):

wherein:

-   -   represents a double or triple bond;    -   Q is —C(═O)—, —C(═NR^(8′))—, —NR⁸C(═O)—, —S(═O)₂— or        —NR⁸S(═O)₂—;

R⁸ is H, C₁-C₆alkyl or hydroxylalkyl;

R^(8′) is H, —OH, —CN or C₁-C₆alkyl;

when

is a double bond then R⁹ and R¹⁰ are each independently H, cyano,carboxyl, C₁-C₆alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl,heteroaryl or hydroxylalkyl or R⁹ and R¹⁰ join to form a carbocyclic orheterocyclic ring;

when

is a triple bond then R⁹ is absent and R¹⁰ is H, C₁-C₆alkyl,aminylalkyl, alkylaminylalkyl or hydroxylalkyl; and

R′ is R¹ and R″ is R^(2c) or R′ is H and R″ is R¹.

In some of the foregoing embodiments of compound (I″a), Q is Q is—C(═O)—, —NR⁸C(═O)—, —S(═O)₂— or —NR⁸S(═O)₂—.

In some other of the foregoing embodiments of compound (I″a), Q is—C(═NR^(8′))—, wherein R^(8′) is H, —OH, —CN or C₁-C₆alkyl. For example,in some embodiments R^(8′) is H. In other embodiments, R^(8′) is —CN. Inother embodiments, R^(8′) is —OH.

In other embodiments, the compound has one of the following structures(I″b), (I″c), (I″d) or (I″e):

In other embodiments, the compound has one of the following structures(I″f), (I″g), (I″h) or (I″i):

In some different embodiments, the compound has one of the followingstructures (I″j), (I″k), (I″1) or (I″m):

In other various embodiments, the compound has the following structure(I′″):

wherein A is NH or S.

For example, in some embodiments, the compound has the followingstructure (I′″a):

wherein:

represents a double or triple bond;

Q is —C(═O)—, —C(═NR^(8′))—, —NR⁸C(═O)—, —S(═O)₂— or —NR⁸S(═O)₂—;

R⁸ is H, C₁-C₆alkyl or hydroxylalkyl;

R⁸ is H, —OH, —CN or C₁-C₆alkyl; and

when

is a double bond then R⁹ and R¹⁰ are each independently H, cyano,carboxyl, C₁-C₆alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl,heteroaryl or hydroxylalkyl or R⁹ and R¹⁰ join to form a carbocyclic orheterocyclic ring;

when

is a triple bond then R⁹ is absent and R¹⁰ is H, C₁-C₆alkyl,aminylalkyl, alkylaminylalkyl or hydroxylalkyl; and

A is NH or S.

In some of the foregoing embodiments of compound (I′″a), Q is Q is—C(═O)—, —NR⁸C(═O)—, —S(═O)₂— or —NR⁸S(═O)₂—.

In some other of the foregoing embodiments of compound (I′″a), Q is—C(═NR^(8′))—, wherein R^(8′) is H, —OH, —CN or C₁-C₆alkyl. For example,in some embodiments R^(8′) is H. In other embodiments, R^(8′) is —CN. Inother embodiments, R^(8′) is —OH.

In other embodiments, the compound has one of the following structures(I′″b), (I′″c), (I′″d) or (I′″e):

In still more embodiments, the compound has one of the followingstructures (I′″f), (I′″g), (I′″h) or (I′″i):

In certain embodiments of any of the foregoing, at least one of G¹ or G²is N. In other embodiments, at least one of W, X or Y is N or NR⁵. Inother embodiments, at least one of W, X or Y is N and at least one of W,X or Y is CR⁶. For example, in some embodiments two of W, X and Y are Nand one of W, X and Y is CR⁶.

In some embodiments, at least one of W, X or Y is N or NR⁵, wherein R⁵is a bond to L¹. In some other embodiments, at least one of W, X or Y isN or CR⁶, wherein R⁶ is a bond to L¹.

For example, in some different embodiments, the compound has one of thefollowing structures:

wherein:

represents a double or triple bond;

Q is —C(═O)—, —C(═NR^(8′))—, —NR⁸C(═O)—, —S(═O)₂— or —NR⁸S(═O)₂—;

R⁸ is H, C₁-C₆alkyl or hydroxylalkyl;

R^(8′) is H, —OH, —CN or C₁-C₆alkyl;

when

is a double bond then R⁹ and R¹⁰ are each independently H, cyano,carboxyl, C₁-C₆alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl,heteroaryl or hydroxylalkyl or R⁹ and R¹⁰ join to form a carbocyclic orheterocyclic ring; and

when

is a triple bond then R⁹ is absent and R¹⁰ is H, C₁-C₆alkyl,aminylalkyl, alkylaminylalkyl or hydroxylalkyl.

In some embodiments of the compounds of structures (I′n), (I′o) or(I′p), R¹ is aryl or heteroaryl and R^(2a) and R^(2b) are independentlyselected from H and halo, for example in some further embodiments R¹ isaryl or heteroaryl and R^(2a) and R^(2b) are independently selected fromhalo, such as chloro and fluoro. In some embodiments, R¹ is aryl orheteroaryl, R^(2a) is chloro and R^(2b) is fluoro. In other embodimentsR¹ is aryl or heteroaryl, one of R^(2a) or R^(2b) is halo, such aschloro or fluoro, and the other one of R^(2a) or R^(2b) is H. In otherembodiments of the foregoing, R⁶ is H, cyano, cyanoalkyl, amino, orC₁-C₆ alkyl.

In other different embodiments, the bond between W and X Y and Z areboth single bonds. For example, in some embodiments the compound has oneof the following structures (I′″″a) or (I′″″b):

wherein:

represents a double or triple bond;

Q is —C(═O)—, —C(═NR^(8′))—, —NR⁸C(═O)—, —S(═O)₂— or —NR⁸S(═O)₂—;

R⁸ is H, C₁-C₆alkyl or hydroxylalkyl;

R^(8′) is H, —OH, —CN or C₁-C₆alkyl;

when

is a double bond then R⁹ and R¹⁰ are each independently H, cyano,carboxyl, C₁-C₆alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl,heteroaryl or hydroxylalkyl or R⁹ and R¹⁰ join to form a carbocyclic orheterocyclic ring; and

when

is a triple bond then R⁹ is absent and R¹⁰ is H, C₁-C₆alkyl,aminylalkyl, alkylaminylalkyl or hydroxylalkyl.

In some embodiments of the compounds of structures (I′″″a) or (I′″″b),R¹ is aryl or heteroaryl and R^(2a) and R^(2b) are independentlyselected from H and halo, for example in some further embodiments R¹ isaryl or heteroaryl and R^(2a) and R^(2b) are independently selected fromhalo, such as chloro and fluoro. In some embodiments, R¹ is aryl orheteroaryl, R^(2a) is chloro and R^(2b) is fluoro. In other embodimentsR¹ is aryl or heteroaryl, one of R^(2a) or R^(2b) is halo, such aschloro or fluoro, and the other one of R^(2a) or R^(2b) is H. In otherembodiments of the foregoing, R⁶ is H, cyano, cyanoalkyl, amino, orC₁-C₆ alkyl.

In yet more of any of the foregoing embodiments, E has the followingstructure:

wherein:

Q is —C(═O)—, —C(═NR^(8′))—, —NR⁸C(═O)—, —S(═O)₂— or —NR₈S(═O)₂—;

R⁸ is H, C₁-C₆alkyl or hydroxylalkyl;

R^(8′) is H, —OH, —CN or C₁-C₆alkyl; and

R⁹ and R¹⁰ are each independently H, cyano, C₁-C₆alkyl, aminylalkyl,alkylaminylalkyl, or hydroxylalkyl or R⁹ and R¹⁰ join to form acarbocyclic or heterocyclic ring.

In some of the foregoing embodiments, Q is Q is —C(═O)—, —NR⁸C(═O)—,—S(═O)₂— or —NR⁸S(═O)₂—.

In some other of the foregoing embodiments, Q is —C(═NR^(8′))—, whereinR^(8′) is H, —OH, —CN or C₁-C₆alkyl. For example, in some embodimentsR^(8′) is H. In other embodiments, R^(8′) is —CN. In other embodiments,R^(8′) is —OH.

In still other of any of the foregoing embodiments, E has the followingstructure:

wherein:

Q is —C(═O)—, —NR⁸C(═O)—, —S(═O)₂— or —NR⁸S(═O)₂—;

R⁸ is H, C₁-C₆alkyl or hydroxylalkyl; and

R¹⁰ is H, C₁-C₆alkyl, aminylalkyl, alkylaminylalkyl or hydroxylalkyl.

In some embodiments of any of the compounds described herein, C₁-C₆haloalkyl is CF₃ (e.g., when one or more of R^(2a), R^(2b) or R^(2c) isC₁-C₆ haloalkyl).

In some embodiments m¹ is 1. In other embodiments m¹ is 2. In still moreembodiments, m¹ is 3. In different embodiments, m² is 1. In some otherembodiments, m² is 2. In yet still more embodiments, m² is 3.

In some other particular embodiments of any of the foregoing compounds,m¹ is 1, and m² is 1. In other embodiments, m¹ is 1 and, m² is 2. Instill other embodiments m¹ is 2, and m² is 2. In more embodiments, m¹ is1, and m² is 3.

In any of the foregoing embodiments, G¹ and G² are each independentlyselected from N and CH. In some embodiments, at least one of G¹ or G² isN. In some embodiments, each of G¹ and G² are N. In some embodiments,each of G¹ and G² are N and m¹ and m² are each 2. In some otherembodiments, at least one of G¹ or G² is CH. In other embodiments, eachof G¹ and G² are CH.

Without wishing to be bound by theory, Applicants believe correctselection of the R¹ substituent may play a part in the compounds'inhibitory activity (e.g., against KRAS, HRAS or NRAS G12C). In someembodiments, R¹ is aryl or hetercyclyl (e.g., heteroaryl or aliphaticheterocyclyl), each of which is optionally substituted with one or moresubstituents. In some embodiments, R¹ is capable of reversibleinteraction with KRAS, HRAS or NRAS G12C mutant protein. In someembodiments R¹ has high affinity towards KRAS, HRAS or NRAS and ishighly specific towards G12C KRAS, HRAS or NRAS. In some embodiments R¹is capable of hydrophobic interaction with KRAS, HRAS or NRAS G12C. Insome embodiments R¹ is able to form hydrogen bonds with various residuesof G12C KRAS, HRAS or NRAS protein.

In other of the foregoing embodiments, R¹ is heterocyclyl, heteroaryl oraryl.

In certain embodiments of any of the foregoing, R¹ is aryl. For example,in some embodiments R¹ is phenyl. In other embodiments, R¹ is napthyl.In some of these embodiments, R¹ is unsubstituted aryl, such asunsubstituted phenyl or unsubstituted napthyl. In other embodiments, R¹is substituted with one or more substituents. In some of theseembodiments, the substituents are selected from halo, cyano, hydroxyl,C₁-C₆alkyl, C₁-C₆alkoxy and C₃-C₈cycloalkyl. In other more specificembodiments, the substituents are selected from fluoro, chloro, bromo,hydroxyl, methoxy and cyclopropyl.

In other embodiments, the R¹ substituents are selected from halo, cyano,cyanoC₁-C₆alkyl, cyanoC₃-C₈cycloalkyl, hydroxyl, C₁-C₆alkyl,C₁-C₆alkylcycloalky, C₂-C₆alkynyl, C₁-C₆alkoxy, C₁-C₆haloalkoxy,C₁-C₆alkylaminyl, C₁-C₆alkylcarbonylaminyl, C₁-C₆hydroxylalkyl,C₁-C₆haloalkyl, C₁-C₆alkoxyalkyl, aminylsulfone, aminylcarbonyl,aminylcarbonylC₁-C₆alkyl, aminylcarbonylC₃-C₈cycloalkyl,C₁-C₆alkylaminylcarbonyl, C₃-C₈cycloalkylaminylcarbonyl,C₃-C₈cycloalkylalkyl and C₃-C₈cycloalkyl, C₃-C₈fused cycloalkyl andheteroaryl.

In still other embodiments, the R¹ substituents are selected fromfluoro, chloro, bromo, cyano, hydroxyl, hydroxylmethyl, methoxy,methoxymethyl, ethyl, isopropyl, trifluoromethyl, aminylcarbonyl andcyclopropyl.

In still more embodiments, the R¹ substituents are selected from fluoro,chloro, bromo, cyano, hydroxyl, hydroxylmethyl, methoxy, methoxymethyl,methyl, ethyl, isopropyl, difluoromethyl, trifluoromethyl,aminylcarbonyl and cyclopropyl.

In certain embodiments, R¹ has one of the following structures:

In other of the foregoing embodiments, R¹ has one of the followingstructures:

In still other embodiments, R¹ has one of the following structures:

In some different embodiments of any of the foregoing, R¹ is heteroaryl.In certain embodiments, R¹ comprises oxygen, sulfur, nitrogen orcombinations thereof. In some of these embodiments, R¹ comprises sulfuror nitrogen. In certain embodiments, R¹ is thiophenyl, pyridinyl,pyridinonyl, pyrimidinyl, benzooxazolyl, benzoisoxazolyl,benzodioxazolyl, benzoimidazolyl, quinolinyl, quinolinonyl,dihydroquinolinonyl, tetrahydroquinolinyl, quinazolinyl, indazolyl,indolinonyl, benzothiophenyl or dihydrobenzodioxinyl.

In some embodiments, R¹ is substituted or unsubstituted indazolyl. Insome of these embodiments the indazolyl is substituted with one or moreC₁-C₆ alkyl, C₁-C₆ alkoxy and/or halo groups. For example, in someembodiments, the indazolyl is substituted with one or more methyl,methoxy, chloro and/or fluoro groups.

For example, in some embodiments R¹ is pyridinyl. In some embodiments R¹is unsubstituted pyridinyl, for example unsubstituted pyridin-4-yl orunsubstituted pyridin-3-yl. In other embodiments R¹ is thiophenyl. Insome embodiments R¹ is unsubstituted thiophenyl, for exampleunsubstituted thiophen-2-yl.

In other embodiments, R¹ is substituted with one or more substituents.For example, in some embodiments, the substituents are selected fromhalo, C₁-C₆alkyl, C₁-C₆alkoxy, or C₂-C₆alkenylcarbonylaminyl. In some ofthese embodiments, the substituents are selected from halo andC₁-C₆alkyl. In other embodiments, the substituents are selected fromfluoro, chloro, amino and methyl. For example, in more specificembodiments, the substituents are selected from chloro and methyl. Inother embodiments at least one R1 substituent is fluoro.

In some embodiments, R¹ has one of the following structures:

In certain embodiments. R¹ has one of the following structures:

In some of the foregoing embodiments, R¹ has one of the followingstructures:

In still other embodiments, R¹ is aliphatic heterocyclyl. In someembodiments the aliphatic heterocyclyl comprises oxygen and/or nitrogen.In some further embodiments, R¹ is morpholinyl. For example, in someembodiments R¹ has the following structure:

In various embodiments of the foregoing, R¹ is unsubstituted.

In some of the foregoing embodiments, R^(2a) is H. In other embodiments,R^(2a) is halo, for example in some embodiments R^(2a) is chloro orfluoro. In still other embodiments of the foregoing, R^(2a) isC₁-C₆alkyl. For example, in some embodiments R^(2a) is C₃-C₈ cycloalkyl,such as cyclopropyl.

In other embodiments of the foregoing compounds, R^(2b) and R^(2c), whenpresent, are H. In different embodiments, R^(2b) and R^(2c), whenpresent, are each independently halo. In yet other embodiments, R^(2b),when present, is halo. In more embodiments, R^(2c), when present, ishalo. In certain of the foregoing embodiments, halo is chloro or fluoro.

The Q moiety is typically selected to optimize the reactivity (i.e.,electrophilicity) of E. In certain of the foregoing embodiments, Q is—C(═O)—. In other embodiments, Q is —S(═O)₂—. In still more embodiments,Q is —NR₈C(═O)—. In still more different embodiments, Q is —NR⁸S(═O)₂—.

In some of the immediately foregoing embodiments, R⁸ is H. In other ofthese embodiments, R⁸ is hydroxylalkyl, for example in some embodimentsthe hydroxylalkyl is 2-hydroxylalkyl.

In some embodiments, Q is —C(═NR^(8′))—, wherein R^(8′) is H, —OH, —CNor C₁-C₆alkyl. For example, in some embodiments R^(8′) is H. In otherembodiments, R^(8′) is —CN.

In other embodiments, R^(8′) is —OH.

In some of any one of the foregoing embodiments, at least one of R⁹ orR¹⁰ is H. For example, in some embodiments each of R⁹ and R¹⁰ are H.

In other of the foregoing embodiments, R¹⁰ is alkylaminylalkyl. In someof these embodiments, R¹⁰ has the following structure:

In other embodiments, R¹⁰ is hydroxylalkyl, such as 2-hydroxylalkyl.

In some other different embodiments of the foregoing embodiments, R⁹ andR¹⁰ join to form a carbocyclic ring. For example, in some of theseembodiments the carbocyclic ring is a cyclopentene, cyclohexene orphenyl ring. In other embodiments, the carbocyclic ring is acyclopentene or cyclohexene ring. In other embodiments, the carbocyclicring is a phenyl ring, for example a phenyl ring having the followingstructure:

In some of any of the foregoing embodiments E is an electrophile capableof bonding with a KRAS, HRAS or NRAS protein comprising G12C mutation.In some embodiments, the electrophile E is capable of forming anirreversible covalent bond with a G12C mutant KRAS, HRAS or NRASprotein. In some cases, the electrophile E may bind with the cysteineresidue at the position 12 of a G12C mutant KRAS, HRAS or NRAS protein.In various embodiments of any of the foregoing, E has one of thefollowing structures:

In other embodiments of any of the foregoing, E has one of the followingstructures:

In different embodiments E has one of the following structures:

In some cases E has one of the following structures:

wherein:

R⁸ is H or C₁-C₆alkyl;

R⁹ is H, cyano or C₁-C₆alkyl, or R⁹ joins with R¹⁰ to form a carbocycle;

R¹⁰ is H or C₁-C₆alkyl or R¹⁰ joins with R⁹ to form a carbocycle and

R^(10a) is H or C₁-C₆alkyl.

In some embodiments E is

In some embodiments E is

In some embodiments E is

In some of any of the foregoing embodiments, L¹ is a bond. In otherembodiments, L¹ is NR⁷. For example, in some of these embodiments, R⁷ isC₁-C₆alkyl. In other embodiments, L¹ is NH.

L² can be selected to provide proper spacing and/or orientation for theE group to form a bond with the KRAS, HRAS or NRAS protein. In some ofthe foregoing embodiments, L² is a bond. In other of the foregoingembodiments, L² is alkylene. In some embodiments, the alkylene issubstituted/In other embodiments the alkylene is unsubstituted. Forexample, in some embodiments L² is CH₂ or CH₂CH₂.

In certain embodiments, R^(3a) and R^(3b) are, at each occurrence,independently H, —OH, —NH₂, —CO₂H, halo, cyano, hydroxylalkly,aminylalkyl, cyanoalkyl, carboxyalkyl or aminylcarbonyl, and R^(4a) andR^(4b) are, at each occurrence, independently H, —OH, —NH₂, —CO₂H, halo,cyano, hydroxylalkly, aminylalkyl, cyanoalkyl, carboxyalkyl oraminylcarbonyl.

In other of the foregoing embodiments, R^(3a) and R^(4a) are, at eachoccurrence, independently H, —OH, hydroxylalkly, cyano, oraminylcarbonyl and R^(3b) and R^(4b) are H.

In certain other embodiments, R^(3a) and R^(4a) are H and R^(3b) andR^(4b) are, at each occurrence, independently H, —OH, —NH₂, —CO₂H, halo,cyano, hydroxylalkly, aminylalkyl, cyanoalkyl, carboxyalkyl oraminylcarbonyl.

In any of the foregoing embodiments, at least one of R^(3a), R^(3b),R^(4a) or R^(4b) is H. In some embodiments, each of R^(3a), R^(3b),R^(4a) and R^(4b) are H.

In some embodiments, R^(3a) is —OH, —NH₂, —CO₂H, halo, cyano,hydroxylalkly, aminylalkyl, cyanoalkyl, carboxyalkyl or aminylcarbonyl,and R^(3b), R^(4a) and R^(4b) are H.

In other embodiments, R^(4a) is —OH, —NH₂, —CO₂H, halo, cyano,hydroxylalkly, aminylalkyl, cyanoalkyl, carboxyalkyl or aminylcarbonyl,and R^(3a), R^(3b) and R^(4b) are H.

In other embodiments, R^(3a) is H, —OH, —NH₂, —CO₂H, halo, cyano,hydroxylalkly, aminylalkyl, cyanoalkyl, carboxyalkyl or aminylcarbonyl,and R^(3b) joins with R^(4b) to form a carbocyclic or heterocyclic ring;

In still more embodiments, R^(4a) is H, —OH, —NH₂, —CO₂H, halo, cyano,hydroxylalkly, aminylalkyl, cyanoalkyl, carboxyalkyl or aminylcarbonyl,and R^(4b) joins with R^(3b) to form a carbocyclic or heterocyclic ring.

In other embodiments, R^(3a) and R^(3b) join to form a carbocyclic orheterocyclic ring. In other embodiments, R^(4a) and R^(4b) join to forma carbocyclic or heterocyclic ring.

In still other embodiments, R^(3a) or R^(4a) is aminylcarbonyl. Forexample, in certain embodiments, the aminylcarbonyl is

In other embodiments, R^(3a) or R^(4a) is cyano. In other embodiments,R^(3a) or R^(4a) is —OH. In other embodiments, R^(3a) or R^(4a) ishydroxylalkyl, for example hydroxylmethyl.

In some embodiments, R⁶ is, at each occurrence, independently H, oxo,cyano, cyanoalkyl, aminyl, aminylalkyl, aminylalkylaminyl,aminylcarbonyl, aminylsulfonyl, —CO₂NR^(a)R^(b), wherein R^(a) andR^(b), are each independently H or C1-C6 alkyl or R^(a) and R^(b) jointo form a carbocyclic or heterocyclic ring, alkylaminyl,haloalkylaminyl, hydroxylalkyaminyl, amindinylalkyl, amidinylalkoxy,amindinylalkylaminyl, guanidinylalkyl, guanidinylalkoxy,guanidinylalkylaminyl, C₁-C₆ alkoxy, aminylalkoxy,alkylcarbonylaminylalkoxy, C₁-C₆ alkyl, heterocyclyl, heterocyclyloxy,heterocyclylalkyloxy, heterocyclylaminyl, heterocyclylalkylaminyl,heteroaryl, heteroaryloxy, heteroarylalkyloxy, heteroarylaminyl,heteroarylalkylaminyl, aryl, aryloxy, arylaminyl, arylalkylaminyl,arylalkyloxy or a bond to L¹.

Each of the foregoing R⁶ moieties may be substituted with one or moresubstituents. For example, in some embodiments the one or moresubstituents are aminyl (e.g., substituted or substituted),alkylcarbonyl aminyl, hydroxyl, haloalkyl or heterocycyclyl (e.g.,substituted or substituted aliphatic heterocycle or substituted orsubstituted heteroaryl). For example, in some embodiments, the R⁶ moietyis C₁-C₆ alkyl, C₁-C₆ alkoxy or alkylaminyl, which is furthersubstituted with alkylcarbonylaminyl, hydroxyl, —CN or haloalkyl. Forexample, in some embodiments, R⁶ has one of the following structures:

wherein X is a bond, —O— or —NR—; each R is independently H orC₁-C₆alkyl and n is an integer from 0 to 6.

Various different R⁶ moities are included in the scope of the compounds.For example, in various embodiments, R⁶ is H. In other embodiments, R⁶is —CN. In more embodiments, R⁶ is methoxy.

In various other embodiments, R⁶ is aminylalkyl, aminylalkyloxy oraminylalkyaminyl. For example, in some embodiments R⁶ has the followingstructures:

wherein X is a bond, —O— or —NR—; each R is independently H orC₁-C₆alkyl and n is an integer from 0 to 6.

In other embodiments, R⁶ is amindinylalkyl, amidinylalkoxy,amindinylalkylaminyl, guanidinylalkyl, guanidinylalkoxy orguanidinylalkylaminyl. For example, in some embodiments R⁶ has one ofthe following structures:

wherein X is a bond, —O— or —NR—; each R is independently H orC₁-C₆alkyl and n is an integer from 0 to 6.

In other embodiments, R⁶ is heterocyclyl, heterocyclyloxy,heterocyclylalkyloxy, heterocyclylaminyl, heterocyclylalkylaminyl,heteroaryl, heteroaryloxy, heteroarylalkyloxy, heteroarylaminyl orheteroarylalkylaminyl. For example, in some embodiments R⁶ has one ofthe following structures:

wherein X is a bond, —O— or —NR—; each R is independently H orC₁-C₆alkyl and n is an integer from 0 to 6.

In some of the foregoing embodiments, X is N. in other of the foregoingembodiments, X is N. In other of the foregoing embodiments, Z is N. Instill more embodiments, X is N and Z is N.

In some embodiments, Z is N and Y is N. In other embodiments, X is N, Zis N, Y is CR⁶, wherein R⁶ is H and W is CR⁶, wherein R⁶ is a bond toL¹. In different embodiments, Z is N and Y is CR⁶, wherein R⁶ is H, W isCR⁶, wherein R⁶ is a bond to L¹ and X is CR⁶, wherein R⁶ is cyano,methoxy or amino.

In other embodiments, Z is N, X is CR⁶ and R⁶ is cyano, Y is CR⁶,wherein R⁶ is H and W is CR⁶, wherein R⁶ is a bond to L¹.

In other embodiments, Y is N, Z is N, W is CR⁶, wherein R⁶ is a bond toL¹ and X is CR⁶, wherein R⁶ is H.

In other of the foregoing embodiments, Z is a bond.

In certain embodiments, Y is NR⁵. In some of these embodiments, R⁵ isC₁-C₆alkyl. In other embodiments, R⁵ is H.

In still other embodiments, X or Y is CR⁶. In some of these embodiments,R⁶ is, at each occurrence, independently H, cyano, amino, C₁-C₆alkoxy ora bond to L¹. In some other of these embodiments, R⁶ is H. In otherembodiments, R⁶ is C₁-C₆alkoxy. In other embodiments, R⁶ is cyano. Inmore embodiments, R⁶ is methoxy. In other embodiments, R⁶ is amino.

In various different embodiments, the compound has one of the structuresset forth in Table 1 below:

TABLE 1 Representative Compounds No. Structure Name Method [M + H]⁺  1

1-(4-(7-chloro-6-(2- chlorophenyl)quinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one A 413.20  2

1-(4-(7-chloro-6-(2- chlorophenyl)quinazolin- 4-ylamino)piperidin-1-yl)prop-2-en-1-one A 427.25  3

1-(4-(6-chloro-5-(2- chlorophenyl)-1H- indazol-3-yl)piperazin-1-yl)prop-2-en-1-one C 401.20  4

1-(4-(7-chloro-6-(4- chlorophenyl)quinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one B 413.25  5

1-(4-(7-chloro-6-(3- chlorophenyl)quinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one B 413.20  6

1-(4-(7-chloro-6-(2,4- dichlorophenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one B 447.20^(#)  7

1-(4-(7-chloro-6-(3,4- dichlorophenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one B 449.15  8

2-(4-(4-acryloylpiperazin- 1-yl)-7-chloroquinazolin- 6-yl)benzonitrile B404.1  9

1-(4-(7-chloro-6-(2,5- dichlorophenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one B 448.45  10

1-(4-(7-chloro-6-(5- chloro-2- hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one B 429.25  11

1-(4-(7-chloro-6-(4- chloro-2- hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one B 429.25  12

1-(4-(7-chloro-6-(4- hydroxyphenyl)quinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one B 395.25  13

1-(4-(7-chloro-6-(4- chloro-2- methoxyphenyl)quinazolin-4-yl)piperazin-1- yl)prop-2-en-1-one B 443.30  14

1-(4-(7-chloro-6-(3- hydroxyphenyl)quinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one B 395.25  15

1-(4-(7-chloro-6-(2- hydroxyphenyl)quinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one B 395.25  16

4-(4-(4-acryloylpiperazin- 1-yl)-7-chloroquinazolin- 6-yl)benzonitrile B404.3  17

1-(4-(7-chloro-6-(pyridin- 4-yl)quinazolin-4- yl)piperazin-1-yl)prop-2-en-1-one B 380.25  18

1-(4-(7-chloro-6- phenylquinazolin-4- yl)piperazin-1-yl)prop-2- en-1-oneB 379.25  19

3-(4-(4-acryloylpiperazin- 1-yl)-7-chloroquinazolin- 6-yl)benzonitrile B404.25  20

1-(4-(7-chloro-6-(pyridin- 3-yl)quinazolin-4- yl)piperazin-1-yl)prop-2-en-1-one B 380.25  21

1-(4-(7-chloro-6- (thiophen-2-yl)quinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one B 385.25  22

1-(4-(5-(2-chlorophenyl)- 4a,7a-dihydrothieno[2,3- d]pyrimidin-4-yl)piperazin-1-yl)prop-2- en-1-one H 385.20  23

1-(4-(7-chloro-6-(2- chloro-5- fluorophenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one B 431.20  24

1-(4-(6-chloro-7-(2- chlorophenyl)isoquinolin- 1-yl)piperazin-1-yl)prop-2-en-1-one D 412.20  25

(E)-1-(4-(7-chloro-(2- chlorophenyl)quinazolin- 4-yl)piperazin-1-yl)-4-(dimethylamino)but-2-en- 1-one A 470.35  26

1-(4-(7-chloro-6-(5- methylthiophen-2- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one B 399.20  27

1-(4-(7-chloro-6-(2- chlorophenyl)quinolin-4- yl)piperazin-1-yl)prop-2-en-1-one E 412.20  28

1-(4-(5-(2-chlorophenyl)- 7,7a-dihydro-4aH- pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop- 2-en-1-one J 368.25  29

N-(1-(7-chloro-6-(2- chlorophenyl)quinazolin- 4-yl)azetidin-3-yl)acrylamide B 399.20  30

1-(3-(7-chloro-6-(2- chlorophenyl)quinazolin- 4-ylamino)azetidin-1-yl)prop-2-en-1-one B 399.20  31

1-(4-(6-chloro-5-(2- chlorophenyl)-1H- indazol-3- ylamino)piperidin-1-yl)prop-2-en-1-one C 413.40⁺  32

1-(4-(7-chloro-6- morpholinoquinazolin-4- yl)piperazin-1-yl)prop-2-en-1-one L 388.25  33

1-(4-(6-(2-chlorophenyl)- 7-fluoroquinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one B 397.20  34

1-(4-(7-chloro-6-(5- chlorothiophen-2- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one B 419.15  35

1-(4-(8-(2- chlorophenyl)quinazolin- 2-yl)piperazin-1-yl)prop-2-en-1-one I 379.1  36

1-(4-(7-chloro-6-(2- chlorophenyl)quinazolin- 4-yl)piperidin-1-yl)prop-2-en-1-one K 410.35⁺  37

1-(4-(6-chloro-7-(4- chlorophenyl)isoquinolin- 1-yl)piperazin-1-yl)prop-2-en-1-one D 412.20  38

1-(4-(6-chloro-7-(4- chloro-2- hydroxyphenyl)isoquinolin-1-yl)piperazin-1- yl)prop-2-en-1-one D 428.25  39

1-(4-(2-amino-7-chloro-6- (4- chlorophenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one F 428.3  40

1-(4-(6-(4-bromophenyl)- 7-chloroquinazolin-4- yl)piperazin-1-yl)prop-2-en-1-one B 459.25  41

1-(4-(7-cyclopropyl-6-(4- cyclopropylphenyl)quinazolin-4-yl)piperazin-1- yl)prop-2-en-1-one B 425.25  42

4-(4-acryloylpiperazin-1- yl)-7-chloro-6-(4- chlorophenyl)quinoline-3-carbonitrile G 437.25  43

1-(4-(7-chloro-6-(4- chlorophenyl)-2- methoxyquinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one F 465.30*  44

1-acryloyl-4-(7-chloro-6- (4- chlorophenyl)quinazolin-4-yl)piperazine-2- carboxamide A 454.35⁺  45

7-chloro-6-(4- chlorophenyl)-4-(4- (vinylsulfonyl)piperazin-1-yl)quinazoline A 449.25  46

1-(4-(7-chloro-6-(4- chlorophenyl)quinazolin- 4-yl)-2-(hydroxymethyl)piperazin- 1-yl)prop-2-en-1-one A 443.30  47

1-acryloyl-4-(7-chloro-6- (4- chlorophenyl)quinazolin-4-yl)piperazine-2- carbonitrile A 438.25  48

1-acryloyl-4-(7- chloroquinazolin-4- yl)piperazine-2- carbonitrile A328.2  49

1-acryloyl-4-(6-bromo-7- chloroquinazolin-4- yl)piperazine-2-carbonitrile A 408.20  50

1-(4-(7-chloro-6-(4- chlorophenyl)-2- methylquinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one M 427.35  51

1-acryloyl-4-(7-chloro-6- (thiophen-2-yl)quinazolin- 4-yl)piperazine-2-carbonitrile A 410.30  52

1-acryloyl-4-(7-chloro-6- phenylquinazolin-4- yl)piperazine-2-carbonitrile A 404.35  53

4-(4-acryloyl-3- cyanopiperazin-1-yl)-7- chloroquinazoline-6-carbonitrile B 353.20  54

(S)-1-acryloyl-4-(7- chloro-6-(4- chlorophenyl)quinazolin-4-yl)piperazine-2- carboxamide A 456.30  55

1-acryloyl-4-(7-chloro-6- cyclopropylquinazolin-4- yl)piperazine-2-carbonitrile B 368.25  56

1-acryloyl-4-(7-chloro-6- (4-chlorophenyl)-2- methylquinazolin-4-yl)piperazine-2- carbonitrile M 452.30  57

1-acryloyl-4-(quinazolin- 4-yl)piperazine-2- carbonitrile A 294.20  58

(R)-1-acryloyl-4-(7- chloro-6-(4- chlorophenyl)quinazolin-4-yl)piperazine-2- carbonitrile A 438.20  59

(S)-1-acryloyl-4-(7- chloro-6-(4- chlorophenyl)quinazolin-4-yl)piperazine-2- carbonitrile A 438.25  60

1-(4-(7-chloro-6-(4- chlorophenyl)quinazolin- 4-yl)-2-((dimethylamino)meth- yl)piperazin- 1-yl)prop-2-en-1- one A 470.35  61

1-acryloyl-4-(6- chloroisoquinolin-1- yl)piperazine-2- carbonitrile D327.20  62

1-(4-(7-chloro-6-(4- chlorophenyl)quinazolin- 4-yl)-2-(2-hydroxyethyl)piperazin-1- yl)prop-2-en-1-one A 457.35  63

(S)-1-(4-(7-chloro-6-(4- chlorophenyl)quinazolin- 4-yl)-2-(hydroxymethyl)piperazin- 1-yl)prop-2-en-1-one A 443.30  64

(R)-1-acryloyl-4-(7- chloro-6-(4- chlorophenyl)quinazolin-4-yl)piperazine-2- carboxamide A 456.30  65

(R)-1-(4-(7-chloro-6-(4- chlorophenyl)quinazolin- 4-yl)-2-(hydroxymethyl)piperazin- 1-yl)prop-2-en-1-one A 443.35  66

(E)-4-(7-chloro-6-(4- chlorophenyl)quinazolin- 4-yl)-1-(4-(dimethylamino)but-2- enoyl)piperazine-2- carbonitrile A 495.40  67

1-(4-(6-chloro-7- phenylquinazolin-4- yl)piperazin-1-yl)prop-2- en-1-oneB 379.30  68

1-(4-(6-chloro-7- cyclopropylquinazolin-4- yl)piperazin-1-yl)prop-2-en-1-one A 343.25  69

2-(1-acryloyl-4-(7-chloro- 6-(4- chlorophenyl)quinazolin-4-yl)piperazin-2- yl)acetamide A 470.35  70

2-(1-acryloyl-4-(7-chloro- 6-(4- chlorophenyl)quinazolin-4-yl)piperazin-2- yl)acetonitrile A 452.35  71

1-(4-(6-(4- chlorophenyl)quinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one A 379.30  72

1-(4-(6-chloro-7-(2- chlorophenyl)quinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one A 413.25  73

1-(4-(6-chloro-7-(3- chlorophenyl)quinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one A 413.3  74

1-(4-(6-chloro-7-(2- hydroxyphenyl)quinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one A 395.25  75

1-(4-(6-chloro-7-(3- hydroxyphenyl)quinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one A 395.25  76

1-(4-(6-chloro-7- phenoxyquinazolin-4- yl)piperazin-1-yl)prop-2-en-1-one L 395.25  77

1-(4-(6-chloro-7-(2- ethylphenyl)quinazolin-4- yl)piperazin-1-yl)prop-2-en-1-one A 407.75  78

1-(4-(6-chloro-7-(4- chlorophenyl)quinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one A 413.25  79

1-(4-(6-chloro-7-(3- ethylphenyl)quinazolin-4- yl)piperazin-1-yl)prop-2-en-1-one A 407.30  80

1-(4-(6-chloro-7- (piperidin-1- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one L 387.25  81

1-(4-(6-chloro-7-(2- fluorophenyl)quinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one A 397.25  82

(E)-1-(4-(6-chloro-7- phenylquinazolin-4- yl)piperazin-1-yl)-4-(dimethylamino)but-2-en- 1-one A 436.40  83

1-(4-(6-chloro-7-(4- fluorophenyl)quinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one A 397.25  84

1-(4-(6-chloro-7-(3- fluorophenyl)quinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one A 397.25  85

2-(1-acryloyl-4-(6-chloro- 7-phenylquinazolin-4- yl)piperazin-2-yl)acetonitrile A 418.30  86

1-(4-(6-cyclopropyl-7- phenylquinazolin-4- yl)piperazin-1-yl)prop-2-en-1-one B 385.75  87

1-(4-(7-phenylquinazolin- 4-yl)piperazin-1-yl)prop- 2-en-1-one B 345.20 88

1-(4-(7-chloro-6- phenylisoquinolin-1- yl)piperazin-1-yl)prop-2-en-1-one D 378.20  89

N-(1-(6-chloro-7- phenylquinazolin-4- yl)piperidin-4- yl)acrylamide B393.25  90

1-(4-(6-chloro-7-(pyridin- 3-yl)quinazolin-4- yl)piperazin-1-yl)prop-2-en-1-one B 380.25  91

1-(4-(6-chloro-7- phenylquinolin-4- yl)piperazin-1-yl)prop-2- en-1-one E378.20  92

1-(4-(6-chloro-7-(pyridin- 2-yl)quinazolin-4- yl)piperazin-1-yl)prop-2-en-1-one B 380.25  93

1-(4-(6-ethyl-7- phenylquinazolin-4- yl)piperazin-1-yl)prop-2- en-1-oneB 373.75  94

1-(4-(6-chloro-2-methoxy- 7-phenylquinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one F 409.30  95

1-(4-(6-chloro-2-methyl- 7-phenylquinazolin-4- yl)piperazin-1-yl)prop-2-en-1-one M 393.70  96

1-(3-(6-chloro-7- phenylquinazolin-4- ylamino)azetidin-1-yl)prop-2-en-1-one A 365.20  97

1-(4-(6-chloro-7-(2- methoxyphenyl)quinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one B 409.7  98

2-(4-(4-acryloylpiperazin- 1-yl)-6-chloroquinazolin- 7-yl)benzamide B422.30  99

1-(4-(6-chloro-7-(2- isopropylphenyl)quinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one B 421.35 100

1-(4-(6-chloro-7-(2- (trifluoromethyl)phe- nyl)quinazolin-4-yl)piperazin- 1-yl)prop-2-en-1-one B 447.80 101

1-(4-(6-chloro-7-(2,5- dichlorophenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one B 447.25 102

1-(4-(6-chloro-7-(2,4- dichlorophenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one B 447.30 103

1-(4-(6-chloro-7-(2- (methoxymethyl)phe- nyl)quinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one B 423.35 104

1-acryloyl-4-(6-chloro-7- phenylquinazolin-4- yl)piperazine-2-carboxamide B 422.35 105

2-(4-(4-acryloylpiperazin- 1-yl)-6-chloroquinazolin- 7-yl)benzonitrile B405.20 106

2-(1-acryloyl-4-(6-chloro- 7-(2- fluorophenyl)quinazolin-4-yl)piperazin-2- yl)acetonitrile B 437.30 107

2-(1-acryloyl-4-(6-chloro- 7-(2- ethylphenyl)quinazolin-4-yl)piperazin-2- yl)acetonitrile B 446.35 108

1-(4-(6-chloro-7-(2- (hydroxymethyl)phe- nyl)quinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one B 409.30 109

2-(1-acryloyl-4-(6-chloro- 7-(2- chlorophenyl)quinazolin-4-yl)piperazin-2- yl)acetonitrile B 452.30 110

2-(1-acryloyl-4-(6-chloro- 7-(4- chlorophenyl)quinazolin-4-yl)piperazin-2- yl)acetonitrile B 452.25 111

2-(1-acryloyl-4-(6-chloro- 7-(4- chlorophenyl)quinazolin-4-yl)piperazin-2- yl)acetonitrile B 452.25 112

1-(4-(6-chloro-7-(2,4- difluorophenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one B 415.0 113

1-(4-(6-chloro-7-(2,5- difluorophenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one B 415.10 114

1-(4-(6-chloro-7-(4- chloro-2- fluorophenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one B 431.05 115

1-(4-(6-chloro-7-(5- chloro-2- fluorophenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one B 431.05 116

1-(4-(6-chloro-7- phenylquinazolin-4-yl)-2- (hydroxymethyl)piperazin-1-yl)prop-2-en-1-one B 409.25 117

1-(4-(6-chloro-7-(4- chloro-2- hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one B 429.35 118

1-(4-(6-chloro-7-(5- chloro-2- hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one B 429.30 119

1-(4-(6-chloro-7-(4- fluoro-2- (trifluoromethyl)phe- nyl)quinazolin-4-yl)piperazin- 1-yl)prop-2-en-1-one B 465.35 120

1-acryloyl-4-(6-chloro-7- (2- fluorophenyl)quinazolin-4-yl)piperazine-2- carboxamide B 440.30 121

1-acryloyl-4-(6-chloro-7- (2- (trifluoromethyl)phe- nyl)quinazolin-4-yl)piperazine- 2-carboxamide B 490.40 122

1-(4-(6-chloro-7-(5- fluoro-2- hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one B 413.30 123

1-(4-(6-chloro-7- (naphthalen-1- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one B 429.35 124

1-(4-(6-chloro-7-(2- (trifluoromethyl)phe- nyl)quinazolin- 4-yl)-2-methylpiperazin-1- yl)prop-2-en-1-one B 461.35 125

2-(1-acryloyl-4-(6-chloro- 7-(2- (trifluoromethyl)phe- nyl)quinazolin-4-yl)piperazin- 2-yl)acetonitrile B 486.40 126

1-(4-(6-chloro-7-(2- cyclopropylphenyl)quinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one B 419.20 127

4-(4-acryloylpiperazin-1- yl)-6-chloro-7-(2- fluorophenyl)quinoline-3-carbonitrile G 421.30 128

1-(4-(6-chloro-7-(2- chloro-5- hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one B 430.10 129

1-(4-(7-(benzo[d]oxazol- 7-yl)-6-chloroquinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one B 420.10 130

3-(4-(4-acryloylpiperazin- 1-yl)-6-chloroquinazolin- 7-yl)benzonitrile B404.10 131

3-(4-(4-acryloylpiperazin- 1-yl)-6-chloroquinazolin- 7-yl)-2-fluoro-N,N-dimethylbenzamide B 468.10 132

1-(4-(6-chloro-7-(2,6- difluorophenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one B 415.3 133

1-(4-(6-chloro-7-(4- fluoro-2- hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one B 413.30 134

1-(4-(6-chloro-7-(2- hydroxyphenyl)quinazolin- 4-yl)-2-methylpiperazin-1-yl)prop-2-en-1-one B 409.30 135

1-(4-(6-chloro-7- (quinolin-5-yl)quinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one B 430.30 136

1-(4-(6-chloro-7- (isoquinolin-5- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one B 430.35 137

4-(4-acryloylpiperazin-1- yl)-7-(2- fluorophenyl)quinazoline-6-carbonitrile B 388.30 138

1-(4-(6-chloro-7-(2- fluoro-6- hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one B 413.25 139

2-(1-acryloyl-4-(6-chloro- 7-(2,4- difluorophenyl)quinazolin-4-yl)piperazin-2- yl)acetonitrile B 454.30 140

1-(4-(6-chloro-7-(5- methyl-1H-indazol-4- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one Q 433.15 141

1-(4-(6-chloro-7-(2- fluoro-5- (trifluoromethoxy)phe- nyl)quinazolin-4-yl)piperazin- 1-yl)prop-2-en-1-one B 481.10 142

3-(4-(4-acryloylpiperazin- 1-yl)-6-chloroquinazolin- 7-yl)-N-cyclopropylbenzamide B 462.20 143

1-(3-(4-(4- acryloylpiperazin-1-yl)-6- chloroquinazolin-7-yl)-4-fluorophenyl)cyclopro- paecarbonitrile B 462.10 144

1-(4-(6-chloro-7-(1H- indazol-5-yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one B 419.25 145

1-acryloyl-4-(6-chloro-7- (2,4- difluorophenyl)quinazolin-4-yl)piperazine-2- carbonitrile B 440.30 146

1-acryloyl-4-(6-chloro-7- (2- hydroxyphenyl)quinazolin-4-yl)piperazine-2- carbonitrile B 420.25 147

1-(4-(6-chloro-7-(5- cyclopropyl-2- fluorophenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one B 437.10 148

1-(4-(6-chloro-7-(5,6,7,8- tetrahydronaphthalen-1- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one B 433.20 149

1-(4-(7-(3- aminobenzo[d]isoxazol-4- yl)-6-chloroquinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one B 435.30 150

1-(4-(7-(2-fluorophenyl)- 6- (trifluoromethyl)quinazolin-4-yl)piperazin-1- yl)prop-2-en-1-one R 431.30 151

1-(1-acryloylpiperidin-4- yl)-7-chloro-6-(2,4-difluorophenyl)quinoxalin- 2(1H)-one S 430.30 152

1-(4-(6-chloro-7-(1H- indazol-7-yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one B 419.30 153

1-(4-(6-chloro-7-(2- hydroxynaphthalen-1- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one Q 445.10 154

1-(4-(6-chloro-7-(2- ethynylphenyl)quinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one B 403.25 155

3-(4-(4-acryloylpiperazin- 1-yl)-6-chloroquinazolin-7-yl)-4-fluorobenzamide B 440.25 156

1-(4-(6-chloro-7-(2- (cyclopropylmethyl)phe- nyl)quinazolin- 4-yl)piperazin-1-yl)prop-2- en-1-one B 433.35 157

1-(4-(7-(2- (trifluoromethyl)phe- nyl)quinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one B 413.10 158

1-(4-(6-chloro-8-fluoro-7- (2- fluorophenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one O 415.25 159

1-(4-(6-chloro-7-(2- fluorophenyl)cinnolin-4- yl)piperazin-1-yl)prop-2-en-1-one N 397.25 160

4-(4-(4-acryloylpiperazin- 1-yl)-6-chloroquinazolin- 7-yl)indolin-2-oneB 434.25 161

2-(2-(4-(4- acryloylpiperazin-1-yl)-6- chloroquinazolin-7-yl)phenyl)acetamide B 436.1 162

1-(4-(6-chloro-7-(1H- indazol-6-yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one B 419.3 163

1-(4-(7-(2-fluorophenyl)- 6-hydroxyquinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one A 379.25 164

4-(4-(7-(2- aminobenzo[d]oxazol-5- yl)-6-chloroquinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one B 435.25 165

1-(4-(7-(1H- benzo[d]imidazol-4-yl)-6- chloroquinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one B 419.30 166

1-(4-(6-(2- (trifluoromethyl)phe- nyl)thieno[3,2- d]pyrimidin-4-yl)piperazin-1-yl)prop-2- en-1-one H 419.10 167

1-(4-(6-chloro-7-(1H- indazol-4-yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one B 419.30 168

2-(2-(4-(4- acryloylpiperazin-1-yl)-6- chloroquinazolin-7-yl)phenyl)acetonitrile B 418.1 169

1-(4-(6-chloro-7-(4- hydroxy-2- (trifluoromethyl)phe- nyl)quinazolin-4-yl)piperazin- 1-yl)prop-2-en-1-one B 463.30 170

3-(4-(4-acryloylpiperazin- 1-yl)-6-chloroquinazolin-7-yl)pyridin-2(1H)-one B 396.25 171

4-(4-acryloylpiperazin-1- yl)-6-chloro-7- (naphthalen-1-yl)quinoline-3-carbonitrile P 453.30 172

4-(4-acryloylpiperazin-1- yl)-6-chloro-7-(2,4- difluorophenyl)quinoline-3-carbonitrile P 439.25 173

4-(4-acryloylpiperazin-1- yl)-6-chloro-7-(2- (trifluoromethyl)phe-nyl)quinoline- 3-carbonitrile P 471.35 174

N-(3-(4-(4- acryloylpiperazin-1-yl)-6- chloroquinazolin-7-yl)-4-fluorophenyl)acetamide B 454.10 175

1-(2-(4-(4- acryloylpiperazin-1-yl)-6- chloroquinazolin-7-yl)phenyl)cyclopro- panecarbonitrile B 444.1 176

1-(2-(4-(4- acryloylpiperazin-1-yl)-6- chloroquinazolin-7-yl)phenyl)cyclopro- panecarboxamide B 462.2 177

1-(4-(4-acryloylpiperazin- 1-yl)-6-chloroquinazolin-7-yl)-5-chloropyridin- 2(1H)-one T 430.20 178

N-(4-(4-(4- acryloylpiperazin-1-yl)-6- chloroquinazolin-7-yl)-5-methylpyrimidin-2- yl)acrylamide B 464.10 179

1-(4-(7-(2-amino-5- methylpyrimidin-4-yl)-6- chloroquinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one B 410.10 180

1-(4-(6-chloro-7,8′- biquinazolin-4- yl)piperazin-1-yl)prop-2- en-1-oneB 431.10 181

1-(4-(4-acryloylpiperazin- 1-yl)-6-chloroquinazolin-7-yl)-4-chloropyridin- 2(1H)-one T 430.10 182

4-(4-acryloylpiperazin-1- yl)-6-chloro-7-(2- hydroxyphenyl)quinoline-3-carbonitrile P 419.15 183

1-(4-(7-(2-(1H-pyrazol-4- yl)phenyl)-6- chloroquinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one B 445.20 184

4-(4-acryloylpiperazin-1- yl)-6-chloro-7-(2-chloro- 5-hydroxyphenyl)quinoline- 3-carbonitrile P 453.15 185

1-(4-(6-chloro-7- (thiophen-2-yl)quinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one B 385.10 186

1-(4-(6-chloro-7-(2- (thiazol-2- yl)phenyl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one U 462.25 187

1-(4-(6-chloro-7-(2- (thiazol-5- yl)phenyl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one U 462.25 188

1-(4-(6-chloro-7-(2- fluoro-5-(1H-pyrazol-4- yl)phenyl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one B 463.20 189

4-(4-acryloylpiperazin-1- yl)-6-chloro-7-(2- fluorophenyl)quinoline-3-carboxamide P 439.60 190

1-(4-(7-(2-amino-4- methylpyrimidin-5-yl)-6- chloroquinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one B 410.10 191

1-(4-(6-chloro-7-(2- methyl-5- (methylamino)phen- yl)quinazolin-4-yl)piperazin-1- yl)prop-2-en-1-one B 422.20 192

2-(4-(4-acryloylpiperazin- 1-yl)-6-chloroquinazolin-7-yl)-3-fluorobenzonitrile B 422.10 193

2-(4-(4-acryloylpiperazin- 1-yl)-6-chloroquinazolin-7-yl)-5-fluorobenzamide B 440.20 194

1-(4-(6-chloro-7-(2- fluoro-6- methoxyphenyl)quinazolin-4-yl)piperazin-1- yl)prop-2-en-1-one B 427.15 195

1-(4-(6-chloro-7-(2,4- difluorophenyl)quinazolin-4-yl)-2-ethynylpiperazin- 1-yl)prop-2-en-1-one B 439.15 196

4-(4-acryloylpiperazin-1- yl)-6-chloro-7-(2-fluoro- 5-hydroxyphenyl)quinoline- 3-carbonitrile P 437.15 197

2-(4-(4-acryloylpiperazin- 1-yl)-6-chloroquinazolin-7-yl)-4-fluorobenzamide B 440.20 198

1-(4-(7- (benzo[b]thiophen-3-yl)- 6-chloroquinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one B 435.15 199

1-(4-(6-chloro-7-(2,3- difluoro-6- methoxyphenyl)quinazolin-4-yl)piperazin-1- yl)prop-2-en-1-one B 445.1 200

1-(4-(6-chloro-7-(2,2- difluorobenzo[d][1,3]dioxol- 4-yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one B 459.10 201

1-(4-(6-chloro-7-(2,3- dihydrobenzo[b][1,4]dioxin- 5-yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one B 437.1 202

1-(4-(6-chloro-7-(2- methoxynaphthalen-1- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one O 459.15 203

1-(4-(6-chloro-7-(2,3- difluoro-6- hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one B 431.10 204

1-(4-(7-(2,4- difluorophenyl)-6- (trifluoromethyl)quinazolin-4-yl)piperazin-1- yl)prop-2-en-1-one B 449.15 205

5-(4-(4-acryloylpiperazin- 1-yl)-6-chloroquinazolin-7-yl)-3,4-dihydroquinolin- 2(1H)-one B 448.15 206

1-(4-(6-chloro-7-(2,4- difluoro-5- hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one U 431.10 207

1-(4-(7-(2-chloro-5- hydroxyphenyl)-6- (trifluoromethyl)quinazolin-4-yl)piperazin-1- yl)prop-2-en-1-one R 463.15 208

1-(4-(7-(2-fluoro-6- hydroxyphenyl)-6- (trifluoromethyl)quinazolin-4-yl)piperazin-1- yl)prop-2-en-1-one R 447.20 209

1-(4-(6-chloro-8-fluoro-7- (2- (trifluoromethyl)phe- nyl)quinazolin-4-yl)piperazin- 1-yl)prop-2-en-1-one O 465.15 210

1-(4-(6,8-dichloro-7-(2- fluorophenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one R 431.10 211

2-(4-(4-acryloylpiperazin- 1-yl)-6- (trifluoromethyl)quinazolin-7-yl)benzamide R 456.15 212

1-(4-(6-(trifluoromethyl)- 7-(2- (trifluoromethyl)phe- nyl)quinazolin-4-yl)piperazin- 1-yl)prop-2-en-1-one R 481.20 213

2-(4-(4-acryloylpiperazin- 1-yl)-6-chloroquinazolin-7-yl)benzenesulfonamide B 458.10 214

1-(4-(6-chloro-7- (quinolin-4-yl)quinazolin- 4-yl)piperazin-1-yl)prop-2-en-1-one Q 430.10 215

1-(4-(6-chloro-3-ethynyl- 7-(2- fluorophenyl)quinolin-4-yl)piperazin-1-yl)prop-2- en-1-one G 430.10 216

1-(4-(6-chloro-7-(3,6- difluoro-2- hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one U 431.15 217

1-(4-(6-chloro-7-(2- chloro-5-hydroxyphenyl)- 8-fluoroquinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one O 447.05 218

1-(4-(7-(2- hydroxynaphthalen-1-yl)- 6- (trifluoromethyl)quinazolin-4-yl)piperazin-1- yl)prop-2-en-1-one R 479.20 219

(E)-1-(4-(6-chloro-7-(2,4- difluorophenyl)quinazolin-4-yl)piperazin-1-yl)-4- (dimethylamino)but-2-en- 1-one O 472.10 220

4-(4-acryloylpiperazin-1- yl)-6-chloro-7-(2-fluoro- 6-hydroxyphenyl)quinoline- 3-carbonitrile P 437.15 221

1-(4-(6-chloro-7-(2,4- difluorophenyl)cinnolin-4-yl)piperazin-1-yl)prop-2- en-1-one N 415.10 222

1-(4-(6-chloro-7-(2-(1- methylcyclopropyl)phe- nyl)quinazolin- 4-yl)piperazin-1-yl)prop-2- en-1-one B 433.20 223

1-(4-(6-chloro-7-(1,2,3,4- tetrahydroquinolin-5- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one B 434.15 224

1-(4-(6-chloro-7-(2,4- difluorophenyl)-8- fluoroquinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one O 433.10 225

1-(4-(6-chloro-7-(2- (trifluoromethyl)phe- nyl)cinnolin-4-yl)piperazin-1- yl)prop-2-en-1-one N 447.05 226

1-(4-(6-chloro-7-(1- methyl-1H-indazol-3- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one B 433.05 227

1-(4-(6-chloro-8-fluoro-7- (2-fluoro-6- hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one O 431.05 228

(E)-1-(4-(6-chloro-7-(2- fluorophenyl)quinazolin-4-yl)piperazin-1-yl)-4- (dimethylamino)but-2-en- 1-one B 454.15 229

(E)-1-(4-(6-chloro-8- fluoro-7-(2- fluorophenyl)quinazolin-4-yl)piperazin-1-yl)-4- (dimethylamino)but-2-en- 1-one O 472.15 230

(E)-4-(dimethylamino)-1- (4-(8-fluoro-6,7-bis(2-fluorophenyl)quinazolin- 4-yl)piperazin-1-yl)but-2- en-1-one O 532.25231

1-(4-(6-chloro-7-(2- fluoro-6- hydroxyphenyl)cinnolin-4-yl)piperazin-1-yl)prop- 2-en-1-one N 413.10 232

2-(4-(4-acryloylpiperazin- 1-yl)-6-chloroquinazolin-7-yl)-3-fluorobenzamide Q 440.10 233

1-(4-(6-chloro-7-(2- hydroxy-6- (trifluoromethyl)phe- nyl)quinazolin-4-yl)piperazin- 1-yl)prop-2-en-1-one B 463.10 234

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one O 451.1 235

1-(4-(6-chloro-8-fluoro-7- (2-hydroxynaphthalen-1- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one O 463.10 236

2-(4-(4-acryloylpiperazin- 1-yl)-6-chloro-8- fluoroquinazolin-7-yl)benzamide O 440.10 237

1-(4-(7-(5-methyl-1H- indazol-4-yl)-6- (trifluoromethyl)quinazolin-4-yl)piperazin-1- yl)prop-2-en-1-one R 467.20 238

1-(4-(6-chloro-7-(5- methyl-1H-indazol-4- yl)cinnolin-4-yl)piperazin-1-yl)prop-2-en-1-one N 433.10 239

(E)-ethyl 4-(4-(6-chloro- 7-(2,4- difluorophenyl)quinazolin-4-yl)piperazin-1-yl)-4- oxobut-2-enoate O 487.10 240

8-(4-(4-acryloylpiperazin- 1-yl)-6-chloroquinazolin-7-yl)quinolin-2(1H)-one U 446.10 241

(E)-2-(4-(6-chloro-7-(2- fluorophenyl)quinazolin- 4-yl)piperazine-1-carbonyl)-4-methylpent-2- enenitrile B 464.10 242

4-(4-acryloylpiperazin-1- yl)-6-chloro-8-fluoro-7- (2-fluorophenyl)quinoline-3- carbonitrile P 439.10 243

2-(1-acryloyl-4-(6-chloro- 8-fluoro-7-(2- (trifluoromethyl)phe-nyl)quinazolin- 4-yl)piperazin- 2-yl)acetonitrile O 504.10 244

1-(4-(6-chloro-7-(5- methoxy-1H-indazol-4- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one B 449.10 245

(E)-2-(4-(6-chloro-7-(2- fluorophenyl)quinazolin- 4-yl)piperazine-1-carbonyl)-3-(thiazol-5- yl)acrylonitrile B 505.10 246

4-(4-acryloylpiperazin-1- yl)-6-chloro-8-fluoro-7- (2-fluoro-6-hydroxyphenyl)quinoline- 3-carbonitrile P 455.15 247

1-(4-(6-chloro-7-(2,4- difluorophenyl)quinazolin-4-yl)piperazin-1-yl)-4- hydroxybut-2-yn-1-one B 443.1 248

1-(4-(6-chloro-8-fluoro-2- (2-hydroxyethylamino)-7-(3-hydroxynaphthalen-1- yl)quinazolin-4- yl)piperazin-1-yl)prop-2-en-1-one AC 522.30 249

1-(4-(6-chloro-7-(3- methoxynaphthalen-1- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one B 459.1 250

1-(4-(6-chloro-7-(2- hydroxy-5,6,7,8- tetrahydronaphthalen-1-yl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one AF 449.10 251

1-(4-(6-chloro-7-(3- hydroxynaphthalen-1- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one P 445.10 252

1-(4-(6-chloro-8-fluoro-7- (2- fluorophenyl)quinazolin-4-yl)-2-ethynylpiperazin- 1-yl)prop-2-en-1-one O 439.10 253

1-(4-(6-chloro-2-(2- (dimethylamino)ethylamino)- 8-fluoro-7-(5-methyl-1H-indazol-4- yl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one AC537.4 254

1-(4-(6-chloro-2- ((dimethylamino)methyl)- 8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one AD 508.3255

1-(4-(6-chloro-7-(5,6- dimethyl-1H-indazol-7- yl)-8-fluoroquinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one Q 465.1 256

1-(4-(6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-2- (hydroxymethyl)piperazin- 1-yl)prop-2-en-1-one O493.3 257

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4- yl)-2-(methylamino)quinazolin- 4-yl)piperazin-1-yl)prop- 2-en-1-one AC 480.2258

1-(4-(6-chloro-7-(2- hydroxynaphthalen-1- yl)cinnolin-4-yl)piperazin-1-yl)prop-2-en-1-one N 445.1 259

(E)-2-(4-(6-chloro-7-(2- fluorophenyl)quinazolin- 4-yl)piperazine-1-carbonyl)-3-(4- methyloxazol-2- yl)acrylonitrile B 503.2 260

4-(4-acryloylpiperazin-1- yl)-6-chloro-7-(2- hydroxynaphthalen-1-yl)quinoline-3-carbonitrile P 469.1 261

(E)-2-(4-(6-chloro-7-(2- fluorophenyl)quinazolin- 4-yl)piperazine-1-carbonyl)-5-hydroxy-4,4- dimethylpent-2-enenitrile B 494.4 262

1-(4-(6-chloro-7-(6- methyl-1H-indazol-4- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one AF 494.3 263

(Z)-4-(4-(6-chloro-7-(2,4- difluorophenyl)quinazolin-4-yl)piperazin-1-yl)-4- oxobut-2-enenitrile B 440.1 264

1-(4-(6-chloro-7-(5- chloro-1H-indazol-7- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one AF 454.1 265

2-(4-(4-acryloylpiperazin- 1-yl)-6-chloroquinazolin- 7-yl)-3-hydroxybenzonitrile AF 420.1 266

1-(4-(6-chloro-7-(6- chloro-1H-indazol-4- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one B 453.1 267

1-(4-(6-chloro-7-(2- fluoro-5-(2- hydroxypropan-2-yl)phenyl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one B 455.1 268

1-(4-(6-chloro-7-(6- methyl-1H-indazol-7- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one AF 433.2 269

4-(4-acry4oylpiperazin-1- yl)-6-chloro-8-fluoro-7-(2-hydroxynaphthalen-1- yl)quinoline-3-carbonitrile P 487.1 270

4-(4-acryloylpiperazin-1- yl)-6-chloro-7-(5-methyl- 1H-indazol-4-yl)quinoline-3-carbonitrile P 457.1 271

1-(4-(8-fluoro-7-(2- fluorophenyl)-6- (trifluoromethyl)quinazolin-4-yl)piperazin-1- yl)prop-2-en-1-one W 449.2 272

1-(4-(6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one Q 463.2 273

1-(4-(8-fluoro-7-(2-fluoro- 6-hydroxyphenyl)-6-(trifluoromethyl)quinazolin- 4-yl)piperazin-1- yl)prop-2-en-1-one W465.2 274

1-(4-(6-chloro-8-fluoro-7- (6-methyl-1H-indazol-7- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one O 451.2 275

1-(4-(6-chloro-8-fluoro-7- (4-fluoro-2- (trifluoromethyl)phe-nyl)quinazolin- 4-yl)piperazin- 1-yl)prop-2-en-1-one O 483.2 276

1-(4-(7-(3-(1H-pyrazol-5- yl)phenyl)-6- chloroquinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one Q 445.2 277

1-(4-(6-chloro-7-(3,6- difluoro-2- hydroxyphenyl)-8- fluoroquinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one O 449.1 278

1-(4-(6-chloro-8-fluoro-7- (2-(2-hydroxypropan-2-yl)phenyl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one O 455.2 279

1-(4-(7-(2-fluoro-6- hydroxyphenyl)-6- (trifluoromethyl)cinnolin-4-yl)piperazin-1-yl)prop- 2-en-1-one X 447.2 280

1-(4-(6-chloro-7-(2,4- difluoro-6- hydroxyphenyl)-8- fluoroquinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one O 449.1 281

1-(4-(6-chloro-8-fluoro-7- (2-fluoro-5-(1H-imidazol-4-yl)phenyl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one O 481.2 282

(E)-2-(4-(6-chloro-8- fluoro-7-(2-fluoro-6- hydroxyphenyl)quinazolin-4-yl)piperazine-1- carbonyl)-4-methylpent-2- enenitrile O 498.2 283

(E)-2-(4-(6-chloro-8- fluoro-7-(2-fluoro-6- hydroxyphenyl)quinazolin-4-yl)piperazine-1- carbonyl)-3-(thiazol-5- yl)acrylonitrile O 539.2 284

(E)-2-(4-(6-chloro-8- fluoro-7-(2-fluoro-6- hydroxyphenyl)quinazolin-4-yl)piperazine-1- carbonyl)-3-(pyridin-2- yl)acrylonitrile O 533.2 285

4-(4-acryloylpiperazin-1- yl)-6-chloro-8-fluoro-7- (2-(trifluoromethyl)phe- nyl)quinoline- 3-carbonitrile P 489.2 286

1-(4-(6,8-dichloro-7-(2- methoxynaphthalen-1- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one V 494.1 287

1-(4-(6-chloro-8-fluoro-7- (2-methoxy-6- methylphenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one Q 441.2 288

1-(4-(6-chloro-8-fluoro-7- (1H-indol-3- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one Q 436.1 289

1-(4-(6-chloro-7-(2- chloro-6-hydroxyphenyl)- 8-fluoroquinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one O 448.0 290

1-(4-(6-chloro-7-(2- chloro-6-methylphenyl)-8- fluoroquinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one Q 427.1 291

4-(4-acryloylpiperazin-1- yl)-6-chloro-8-fluoro-7-(3-hydroxynaphthalen-1- yl)quinoline-3-carbonitrile P 487.1 292

1-(4-(7-(2,4- difluorophenyl)-8-fluoro- 6-methylquinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one AJ 413.2 293

4-(4-acryloylpiperazin-1- yl)-6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4- yl)quinoline-3-carbonitrile P 475.2 294

2-(1-acryloyl-4-(6-chloro- 8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4- yl)piperazin-2- yl)acetonitrile O 490.2 295

(E)-1-(4-(6-chloro-8- fluoro-7-(5-methyl-1H- indazol-4-yl)quinazolin-4-yl)piperazin-1-yl)-4- (dimethylamino)but-2-en- 1-one O 508.2 296

1-(4-(7-(2,4- difluorophenyl)-6,8- difluoroquinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one Y 417.22 297

1-(4-(6,8-difluoro-7-(5- methyl-1H-indazol-4- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one Y 435.3 298

1-(4-(6,8-difluoro-7-(6- methyl-1H-indazol-7- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one Y 435.3 299

1-(4-(6,8-difluoro-7-(2- fluoro-6- hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one Y 415.3 300

1-(4-(6-chloro-7-(5- methyl-1H-indazol-4-yl)- 2-(tetrahydrofuran-3-yloxy)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one F 519.3 301

(E)-1-(4-(6-chloro-8- fluoro-7-(2-fluoro-6- hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)-4- (dimethylamino)but-2-en- 1-one O 488.2 302

1-(4-(6-chloro-8-methoxy- 7-(5-methyl-1H-indazol- 4-yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one Z 463.3 303

1-(4-(6,8-dichloro-7-(2- hydroxynaphthalen-1- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one V 479.1 304

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4- yl)-2-(1H-pyrazol-4-yl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one AG 517.0 305

1-(4-(7-(5-methyl-1H- indazol-4-yl)-6- (trifluoromethyl)cinnolin-4-yl)piperazin-1-yl)prop- 2-en-1-one X 467.2 306

1-(4-(6-chloro-7-(2,4- difluorophenyl)-8- methoxyquinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one Z 445.2 307

1-(4-(6-chloro-7-(5- (difluoromethyl)-2- fluorophenyl)-8-fluoroquinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one O 461.2 308

4-(4-acryloylpiperazin-1- yl)-6-chloro-8-fluoro-7-(6-methyl-1H-indazol-7- yl)quinoline-3-carbonitrile P 475.1 309

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4- yl)-2-(1H-pyrazol-5-yl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one AG 517.1 310

(E)-6-chloro-4-(4-(4- (dimethylamino)but-2- enoyl)piperazin-1-yl)-8-fluoro-7-(3- hydroxynaphthalen-1- yl)quinoline-3-carbonitrile P 544.2311

(E)-4-amino-1-(4-(6- chloro-8-fluoro-7-(5- methyl-1H-indazol-4-yl)quinazolin-4- yl)piperazin-1-yl)but-2- en-1-one O 480.2 312

1-(4-(6-chloro-7-(5- methyl-1H-indazol-4-yl)- 2-(methylamino)quinazolin- 4-yl)piperazin-1-yl)prop- 2-en-1-one F 462.3313

1-(4-(6-chloro-7-(2- fluoro-6-hydroxyphenyl)- 8-methoxyquinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one Z 443.2 314

1-(4-(6-chloro-2-(2- (dimethylamino)ethoxy)- 7-(5-methyl-1H-indazol-4-yl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one F 520.4 315

(E)-1-(4-(6-chloro-8- fluoro-7-(5-methyl-1H- indazol-4-yl)quinazolin-4-yl)piperazin-1-yl)-4- hydroxybut-2-en-1-one O 481.3 316

1-(4-(6-chloro-7-(5- methyl-1H-indazol-4-yl)- 2-(tetrahydro-2H-pyran-3-yloxy)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one F 533.3 317

(E)-6-chloro-4-(4-(4- (dimethylamino)but-2- enoyl)piperazin-1-yl)-8-fluoro-7-(5-methyl-1H- indazol-4-yl)quinoline-3- carbonitrile P 532.3318

1-(4-(6-chloro-7-(2- fluoro-6-hydroxyphenyl)- 5-(trifluoromethyl)quinazolin- 4-yl)piperazin-1- yl)prop-2-en-1-one AA481.1 319

1-(4-(2-amino-6-chloro-7- (5-methyl-1H-indazol-4- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one F 448.2 320

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl)quinazolin-4-yl)-2- (hydroxymethyl)piperazin- 1-yl)prop-2-en-1-one O481.2 321

1-(4-(6-chloro-7-(2,4- difluorophenyl)-8- hydroxyquinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one Z 431.1 322

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4- yl)-2-(1-methyl-1H-pyrazol-4- ylamino)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one F546.2 323

1-(4-(6-chloro-2-(2- (dimethylamino)ethoxy)- 8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one F 538.2324

1-(4-(6-chloro-8-fluoro-7- (3-methyl-1H-indazol-7- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one B 451.1 325

(E)-1-(4-(6-chloro-8- fluoro-7-(3- hydroxynaphthalen-1- yl)quinazolin-4-yl)piperazin-1-yl)-4- (dimethylamino)but-2-en- 1-one O 520.3 326

4-(4-acryloylpiperazin-1- yl)-6-chloro-7-(5-methyl-1H-indazol-4-yl)quinolin- 2(1H)-one AB 448.2 327

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl)quinazolin-4-yl)-2- methylpiperazin-1- yl)prop-2-en-1-one O 465.2 328

(E)-1-(4-(6-chloro-8- fluoro-7-(3- hydroxynaphthalen-1- yl)quinazolin-4-yl)piperazin-1-yl)but-2- en-1-one O 477.2 329

1-(4-(6-chloro-2-(3- (dimethylamino)propoxy)- 7-(5-methyl-1H-indazol-4-yl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one F 534.3 330

1-(4-(6-chloro-7-(5- methyl-1H-indazol-4-yl)- 2-(tetrahydrofuran-3-ylamino)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one F 518.3 331

1-(4-(6-chloro-8-fluoro-7- (5-fluoro-1H-indazol-4- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one Q 455.1 332

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4- yl)-2-(thiazol-5-yl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one AG 534.1 333

(E)-1-(4-(6-chloro-8- fluoro-7-(5-methyl-1H- indazol-4-yl)-2-(thiazol-5-yl)quinazolin-4- yl)piperazin-1-yl)-4- (dimethylamino)but-2-en- 1-one AG591.1 334

(R)-1-(4-(6-chloro-8- fluoro-7-(5-methyl-1H- indazol-4-yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one O 451.2 335

(E)-4-amino-1-(4-(6- chloro-8-fluoro-7-(3- hydroxynaphthalen-1-yl)quinazolin-4- yl)piperazin-1-yl)but-2- en-1-one O 492.2 336

4-(4-acryloyl-3- methylpiperazin-1-yl)-6- chloro-8-fluoro-7-(5-methyl-1H-indazol-4- yl)quinoline-3-carbonitrile P 489.2 337

1-(4-(6-chloro-7-(3- (difluoromethyl)naphthalen- 1-yl)-8-fluoroquinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one O 497.2 338

1-(4-(6-chloro-2- (dimethylamino)-8-fluoro- 7-(5-methyl-1H-indazol-4-yl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one AC 494.4 339

1-(4-(6-chloro-2-(3- (dimethylamino)propoxy)- 8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one B 552.2340

1-(4-(6-chloro-8-fluoro-7- (3-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one AH 469.1341

1-(4-(6-chloro-2-(2- (dimethylamino)ethoxy)- 8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin- 4-yl)piperazin-1-yl)prop- 2-en-1-one F 518.2342

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4- yl)-2-(2-morpholinoethoxy)quinazolin- 4-yl)piperazin-1- yl)prop-2-en-1-one F580.2 343

1-(4-(6-chloro-5-fluoro-7- (2-fluoro-6- hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one AD 431.2 344

1-(4-(6-chloro-2- (dimethylamino)-8-fluoro- 7-(3-hydroxynaphthalen-1-yl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one AC 506.3 345

1-(4-(6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1- yl)-2-(methylamino)quinazolin- 4-yl)piperazin-1-yl)prop- 2-en-1-one AC 492.2346

1-(4-(6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl)quinazolin-4-yl)-2- ((dimethylamino)meth- yl)piperazin-1-yl)prop-2-en-1- one O 520.2 347

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl)-2-(tetrahydrofuran-3- ylamino)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one AC 536.3 348

1-(4-(6-chloro-7-(3- hydroxynaphthalen-1-yl)- 8-methoxyquinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one Z 475.3 349

1-(4-(6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1- yl)-2-(1-(2,2,2-trifluoroethyl)pyrrolidin- 3-ylamino)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one AC 629.3 350

1-(4-(7-(5-methyl-1H- indazol-4-yl)-6- (trifluoromethyl)cinnolin-4-yl)piperazin-1-yl)prop- 2-en-1-one X 467.3 351

1-(4-(7-(3- hydroxynaphthalen-1-yl)- 6- (trifluoromethyl)cinnolin-4-yl)piperazin-1-yl)prop- 2-en-1-one X 479.2 352

1-(4-(6-chloro-8-fluoro-2- (2-(1-methyl-1H- imidazol-2-yl)ethylamino)-7-(5- methyl-1H-indazol-4- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one F 575.2 353

(S)-1-(4-(6-chloro-8- fluoro-7-(2-fluoro-6- hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one O 431.2 354

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4- yl)-2-(1-(2,2,2-trifluoroethyl)pyrrolidin- 3-ylamino)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one AC 617.3 355

1-(4-(6-chloro-2-(2- (dimethylamino)ethylamino)- 8-fluoro-7-(3-hydroxynaphthalen-1- yl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-oneAC 549.3 356

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4- yl)-2-(2,2,2-trifluoroethylamino)quinazolin- 4-yl)piperazin-1- yl)prop-2-en-1-one AC548.3 357

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4- yl)-2-(3-morpholinopropoxy)quinazolin- 4-yl)piperazin-1- yl)prop-2-en-1-one F594.2 358

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl)-2-(2-(pyrrolidin-1- yl)ethoxy)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one F 564.2 359

1-(4-(6-chloro-8-fluoro-7- (6-fluoro-3-methyl-1H-indazol-7-yl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one B 469.1360

1-(4-(6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1-yl)-2-(1-methylpyrrolidin- 3-ylamino)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one AC 561.4 361

1-(4-(6-chloro-2-((2- (dimethylamino)ethyl)(meth- yl)amino)-8-fluoro-7-(3- hydroxynaphthalen-1- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one AC 563.4 362

1-(4-(6-chloro-7-(2- ((dimethylamino)methyl)- 6-fluorophenyl)-8-fluoroquinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one O 472.3 363

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl)-2-(1-methylpiperidin- 4-ylamino)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one AC 563.4 364

1-(4-(6-chloro-8-fluoro-7- (3-hydroxynaphthalen-1- yl)-2-(3,3,3-trifluoropropylami- no)quiazolin- 4-yl)piperazin-1- yl)prop-2-en-1-oneAC 560.30 365

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4- yl)-2-(tetrahydro-2H-pyran-4- ylamino)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one AC550.30 366

N-(2-(4-(4- acryloylpiperazin-1-yl)-6- chloro-8-fluoro-7-(5-methyl-1H-indazol-4- yl)quinazolin-2- yloxy)ethyl)acetamide AC 552.35367

1-(4-(6-chloro-2-(2- (dimethylamino)ethoxy)- 8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4- yl)-2-methylpiperazin-1- yl)prop-2-en-1-one F552.30 368

1-(4-(6-chloro-8-fluoro-7- (6-fluoro-1H-indazol-7- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one B 455.1 369

1-(4-(6-chloro-8-fluoro-2- (2-(1-methyl-1H- imidazol-2-yl)ethoxy)-7-(5-methyl-1H-indazol-4- yl)quinazolin-4- yl)piperazin-1-yl)prop-2-en-1-one F 575.2 370

(R)-1-(4-(6-chloro-8- fluoro-7-(2-fluoro-6- hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop- 2-en-1-one O 431.2 371

1-(4-(6-chloro-2-((2- (dimethylamino)ethyl)(meth- yl)amino)-8-fluoro-7-(5- methyl-1H-indazol-4- yl)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one AC 551.35 372

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4-yl)-2-(1-methylpyrrolidin- 3-ylamino)quinazolin-4-yl)piperazin-1-yl)prop-2- en-1-one AC 549.30 373

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4- yl)-2-(2-(4-methylpiperazin-1- yl)ethoxy)quinazolin-4- yl)piperazin-1-yl)prop-2-en-1-one F 593.30 374

1-(4-(6-chloro-2-(2- (dimethylamino)ethoxy)- 8-fluoro-7-(3-hydroxynaphthalen-1- yl)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-oneF 550.25 375

1-(4-(6-chloro-8-fluoro-7- (5-methyl-1H-indazol-4- yl)-2-(1-methyl-1H-pyrazol-4- yloxy)quinazolin-4- yl)piperazin-1-yl)prop-2- en-1-one F547.25 376

4-(4-acryloylpiperazin-1- yl)-6-chloro-8-fluoro-7-(3-hydroxynaphthalen-1- yl)quinazoline-2- carbonitrile AI 488.15 *[M +Na]⁺ ⁺[M − H]⁻ ^(#)[M]

The compounds in Table 1 were each prepared and analyzed by massspectrometry and/or ¹H NMR. Experimental mass spectrometry data isincluded in Table 1 above. Exemplary synthetic procedures are describedin more detail below and in the Examples. General methods by which thecompounds may be prepared are provided below and indicated in Table 1above.

It is understood that in the present description, combinations ofsubstituents and/or variables of the depicted formulae are permissibleonly if such contributions result in stable compounds.

It will also be appreciated by those skilled in the art that in theprocesses for preparing the compounds described herein the functionalgroups of intermediate compounds may need to be protected by suitableprotecting groups. Such functional groups include, but are not limitedto, hydroxy, amino, mercapto and carboxylic acid. Suitable protectinggroups for hydroxy include trialkylsilyl or diarylalkylsilyl (forexample, t-butyldimethylsilyl, t-butyldiphenylsilyl or trimethylsilyl),tetrahydropyranyl, benzyl, and the like. Suitable protecting groups foramino, amidino and guanidino include t-butoxycarbonyl,benzyloxycarbonyl, and the like. Suitable protecting groups for mercaptoinclude —C(O)—R″ (where R″ is alkyl, aryl or arylalkyl),p-methoxybenzyl, trityl and the like. Suitable protecting groups forcarboxylic acid include alkyl, aryl or arylalkyl esters. Protectinggroups are optionally added or removed in accordance with standardtechniques, which are known to one skilled in the art and as describedherein. The use of protecting groups is described in detail in Green, T.W. and P. G. M. Wutz, Protective Groups in Organic Synthesis (1999), 3rdEd., Wiley. As one of skill in the art would appreciate, the protectinggroup may also be a polymer resin such as a Wang resin, Rink resin or a2-chlorotrityl-chloride resin.

It will also be appreciated by those skilled in the art, although suchprotected derivatives of compounds of this invention may not possesspharmacological activity as such, they may be administered to a mammaland thereafter metabolized in the body to form compounds of theinvention which are pharmacologically active. Such derivatives maytherefore be described as “prodrugs”. All prodrugs of compounds of thisinvention are included within the scope of the invention.

Furthermore, all compounds of the invention which exist in free base oracid form can be converted to their pharmaceutically acceptable salts bytreatment with the appropriate inorganic or organic base or acid bymethods known to one skilled in the art.

Salts of the compounds of the invention can be converted to their freebase or acid form by standard techniques.

The following General Reaction Schemes illustrate exemplary methods ofmaking compounds of compounds of structure (I):

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,wherein R¹, R^(2a), R^(3a), R^(3b), R^(4a), R^(4b), G¹, G², L¹, L², m¹,m², A, B, W, X, Y, Z and E are as defined above. For ease ofillustration, many of the schemes which follow illustrate an “R²”moiety. The R2 moiety is meant to include any one of R^(2a), R^(2b) orR^(2c). It is understood that one skilled in the art may be able to makethese compounds by similar methods or by combining other methods knownto one skilled in the art. It is also understood that one skilled in theart would be able to make, in a similar manner as described below, othercompounds of structure (I) not specifically illustrated below by usingthe appropriate starting components and modifying the parameters of thesynthesis as needed. In general, starting components may be obtainedfrom sources such as Sigma Aldrich, Lancaster Synthesis, Inc.,Maybridge, Matrix Scientific, TCI, and Fluorochem USA, etc. orsynthesized according to sources known to those skilled in the art (see,for example, Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, 5th edition (Wiley, December 2000)) or prepared as describedin this invention.

Embodiments of the compound of structure (I) (e.g., compound A-7) can beprepared according to General Reaction Scheme 1 (“Method A”), whereinR¹, R², R^(3a), R^(3b)R^(4a), R^(4b), R⁹, R¹⁰, Q, m¹ and m² are asdefined herein above. As shown in General Reaction Scheme 1, compoundsof structure A-1 can be purchased from commercial sources or preparedaccording to methods familiar to one of ordinary skill in the art.Reaction of A-1 under Suzuki conditions yields A-2. Reaction ofcompounds of structure A-2 with formamide or other suitable reagents,such as formamidine acetate or trimethyl orthoformate, yieldsquinazolines of structure A-3. A-3 is chlorinated under appropriateconditions (e.g., SOCl₂, POCl₃/PCl₅ or POCl₃) to yield chloroqinazolineA-4. Reaction of A-4 with an appropriately protected heterocycle underbasic conditions yields A-5. Appropriate protecting groups includebutyloxycarbonyl (BOC) as depicted in General reaction Scheme 1, as wellas other protecting groups known in the art. Deprotection of A-5followed by acylation with an acid chloride (or sulfonyl chloride) oracid and appropriate activating reagents yields A-7.

Alternatively, embodiments of the compound of structure (I) (e.g.,compound A-7) can be prepared according to General Reaction Scheme 2(“Method B”), wherein R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R⁹, R¹⁰,Q, m¹ and m² are as defined herein above. Compounds of structure A-1 areprepared or purchased as described above. Treatment of A-1 withformamide or other suitable reagents, such as formamidine acetate ortrimethyl orthoformate, yields quinazolines of structure B-1. B-1 canthen be chlorinated to yield B-2 and reacted with an appropriatelyprotected heterocycle under basic conditions to yield B-3 as describedabove for Method A. Suzuki coupling then yields A-5 which can beconverted to A-7 as described in Method A above.

Other embodiments of the compound of structure (I) (e.g., compound C-6)can be prepared according to General Reaction Scheme 3 (“Method C”),wherein R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R⁹, R¹⁰, Q, m¹ and m²are as defined herein above. As shown in General Reaction Scheme 3,compounds of structure C-1, which can be purchased from commercialsources or prepared according to well-known procedures, are reacted withtosyl hydrazine to yield C-2. Chlorination of C-2 with an appropriatereagent(s), such as thionyl chloride, then yields C-3 which can bereacted under basic conditions with an appropriately protectedheterocycle (PG=protecting group or C₁-C₆alkyl) to yield indazole C-4.The tosyl group is removed from C-4 by treatment with sodium hydroxidein THF/H₂O to yield C-5. Removal of the nitrogen protecting group andacylation or thioacylation as described in Method A then yields thedesired compound C-6.

Other embodiments of the compound of structure (I) (e.g., compound D-9)can be prepared according to General Reaction Scheme 4 (“Method D”),wherein R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R⁹, R¹⁰, Q, m¹ and m²are as defined herein above. As shown in General Reaction Scheme 4,benzaldehyde D-1 is treated under reductive amination conditions toyield D-2. Formation of the tosyl-protected amine (D-3) followed bytreatment with an appropriate Lewis acid (e.g., AlCl₃) yieldsisoquinoline D-4. Oxidation of D-4 with meta-chloroperbenzoic acid(mCPBA) yields D-5 which can be chlorinated by treatment with anappropriate reagent, such as POCl₃. Chloride D-6 is then treated in amanner analogous to that described for Method B to yield D-9.

Other embodiments of the compound of structure (I) (e.g., compound E-9)can be prepared according to General Reaction Scheme 5 (“Method E”),wherein R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R⁹, R¹⁰, Q, m¹ and m²are as defined herein above. As shown in General Reaction Scheme 5,aniline E-1, which can be purchased from commercial sources or preparedvia well-known procedures, can be reacted with diethyl2-(ethoxymethylene)malonate to yield E-2. E-2 can then be cyclized byheating in an appropriate high-boiling solvent (e.g., Ph₂O) to yieldquinolone E-3. Saponification of E-3 followed by decarboxylation yieldsE-4 and E-5, respectively. E-5 is then treated in a manner analogous tothat described for Method B to yield E-9.

Other embodiments of the compound of structure (I) (e.g., compound F-6)can be prepared according to General Reaction Scheme 6 (“Method F”),wherein R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R⁹, R¹⁰, Q, m¹ and m²are as defined herein above. As shown in General Reaction Scheme 6, A-1is cyclized to quinazolinedione F-1 by treatment with urea. Chlorinationof F-1 by treatment with POCl₃ followed by reaction with a protectedheterocycle yield F-2 and F-3, respectively. The R⁶ substituent isinstalled by S_(N)Ar reaction of G-3 with LG-R6, wherein LG is anappropriate leaving group. For example, where R⁶ is cyano or alkoxy, LGis sodium or another appropriate action. The general proceduresdescribed above with respect to Method B can then be employed to yieldF-6.

Other embodiments of the compound of structure (I) (e.g., compound G-4)can be prepared according to General Reaction Scheme 7 (“Method G”),wherein R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R⁹, R¹⁰, Q, m¹ and m²are as defined herein above. As shown in General Reaction Scheme 7,aniline E-1 is treated under Suzuki conditions to install the R-1substituent. G-1 is then heated in toluene with an appropriatelysubstituted unsaturated ester to yield G-2. Cyclization of G-2 tohydroxyquinoline G-3 is accomplished by heating in a high boilingsolvent (e.g., Ph₂O) for an appropriate amount of time. Following thegeneral procedures outlined in Method A then yields G-4.

Other embodiments of the compound of structure (I) (e.g., compound H-3)can be prepared according to General Reaction Scheme 8 (“Method H”),wherein R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R⁹, R¹⁰, Q, m¹ and m²are as defined herein above. Referring to General Reaction Scheme 8,thienopyrimidine H-1 can be prepared according to well-known proceduresor purchased from commercial sources. H-1 is treated with anappropriately protected heterocycle under basic conditions to yield H-2.Deprotection followed by acylation or thioacylation according to theprocedures described above then yields H-3.

Other embodiments of the compound of structure (I) (e.g., compound I-4)can be prepared according to General Reaction Scheme 9 (“Method I”),wherein R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R⁹, R¹⁰, Q, m¹ and m²are as defined herein above. Referring to General Reaction Scheme 9,quinazoline I-1 can be prepared according to well-known procedures orpurchased from commercial sources. I-1 is treated with an appropriatelyprotected heterocycle under basic conditions to yield I-2. Suzukireaction of I-2 with an appropriate reagent to install the R¹ moietyresults in I-3. I-3 is then deprotected and acylated (or thioacylated)according to the procedures described above to yield I-4.

Other embodiments of the compound of structure (I) (e.g., compound J-6)can be prepared according to General Reaction Scheme 10 (“Method J”),wherein R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R⁹, R¹⁰, Q, m¹ and m²are as defined herein above. Referring to General Reaction Scheme 10,pyrrolopyrimidinone J-1 can be prepared according to well-knownprocedures or purchased from commercial sources. J-1 is chlorinated withan appropriate reagent (e.g., POCl3) to yield J-2 which is theniodinated with an appropriate reagent, such as N-iodosuccinimide (NIS)to yield J-3. Protection of J-3 followed by Suzuki reaction yields J-5.J-5 is then treated according to the procedures described above to yieldJ-6.

Other embodiments of the compound of structure (I) (e.g., compound K-5)can be prepared according to General Reaction Scheme 11 (“Method K”),wherein R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R⁹, R¹⁰, Q, m¹ and m²are as defined herein above. Referring to General Reaction Scheme 11,quinazoline K-1 can be prepared according to well-known procedures orpurchased from commercial sources. K-1 is reacted with an appropriateester under basic conditions to form the requisite carbon-carbon bond.K-2 is then decarboxylated to yield K-3. Suzuki reaction, deprotectionand acylation or thioacylation are then carried out as described in theabove schemes to yield K-5.

Other embodiments of the compound of structure (I) (e.g., compound L-2)can be prepared according to General Reaction Scheme 12 (“Method L”),wherein R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R⁹, R¹⁰, Q, m¹ and m²are as defined herein above. Specifically, compounds wherein R¹ is aN-heterocycle can be efficiently prepared according to Method L.Referring to General Reaction Scheme 12, compound B-3 is preparedaccording to Method B and treated under Buchwald conditions (where R¹—His a N-heterocycle or alkylaminyl) to yield L-1. Methods for Buchwaldreactions are well-known in the art. L-1 is then converted to L-2according to the above general procedures.

Other embodiments of the compound of structure (I) (e.g., compound M-3)can be prepared according to General Reaction Scheme 13 (“Method M”),wherein R¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R⁶, R⁹, R¹⁰, Q, m¹ andm² are as defined herein above. Referring to General Reaction Scheme 13,compound A-1 is reacted an appropriate nitrile (R6CN) to form compoundM-1. In this regard, R⁶ may be any of the R⁶ moieties described herein,for example alkyl. M-1 is chlorinated by reaction with an appropriatereagent such as thionyl chloride. Compound M-3 is then preparedaccording to the general procedures outlined herein, for example theprocedures of General Reaction Scheme 2.

Embodiments of the compound of structure (I) (e.g., compound N-7) can beprepared according to General Reaction Scheme 14 (“Method N”), whereinR¹, R², R^(3a), R^(3b), R^(4a), R^(4b), R⁹, R¹⁰, Q, m¹ and m² are asdefined herein above. As shown in General Reaction Scheme 14, compoundsof structure N-1 can be purchased from commercial sources or preparedaccording to methods familiar to one of ordinary skill in the art.Compound N-1 is reacted with methylnitrite to form compound N-2.Reaction of N-2 with sodium nitrite under acidic conditions yieldscinnolines of structure N-3. N-3 is chlorinated under appropriateconditions (e.g., SOCl₂, POCl₃/PCl₅ or POCl₃) to yield thechlorocinnoline N-4. Reaction of N-4 with an appropriately protectedheterocycle under basic conditions yields N-5. Appropriate protectinggroups include butyloxycarbonyl (BOC) as depicted in General reactionScheme 1, as well as other protecting groups known in the art. Suzukireaction of N-5 with an appropriate reagent to install the R¹ moietyresults in N-6. Deprotection of N-6 followed by acylation with an acidchloride (or sulfonyl chloride) or acid and appropriate activatingreagents yields N-7.

Embodiments of the compound of structure (I) (e.g., compound O-11) canbe prepared according to General Reaction Scheme 15 (“Method 0”),wherein R¹, R^(2b), R^(3a), R^(3b), R^(4a), R^(4b), R⁹, R¹⁰, Q, m¹ andm² are as defined herein above. As shown in General Reaction Scheme 15,compounds of structure O-1 can be purchased from commercial sources orprepared according to methods familiar to one of ordinary skill in theart. Compound O-1 is reduced to form compound O-2. Reaction of O-2 with2,2,2-trichloroethane-1,1-diol under acidic conditions, thenhydroxylamine hydrochloride, yields O-3. O-3 is cyclized in the presenceof acid to yield O-4. O-4 is reacted in the presence H₂O₂ under basicconditions to yield O-5. O-5 is chlorinated using N-chlorosuccinimide toyield O-6. Reaction of O-6 with formamide or other suitable reagentssuch as formamidine acetate or trimethyl orthoformate yields thequinazolin-4(3H)-one, O-7. O-7 is chlorinated under appropriateconditions (e.g., SOCl₂, POCl₃/PCl₅ or POCl₃) to yield thechloroquinazoline, O-8. Reaction of O-8 with an appropriately protectedheterocycle under basic conditions yields O-9. Appropriate protectinggroups include butyloxycarbonyl (BOC) as depicted in General reactionScheme 1, as well as other protecting groups known in the art. Suzukireaction of O-9 with an appropriate reagent to install the R¹ moietyresults in O-10. Deprotection of O-10 followed by acylation with an acidchloride (or sulfonyl chloride) or acid and appropriate activatingreagents yields O-11.

Embodiments of the compound of structure (I) (e.g., compound P-10) canbe prepared according to General Reaction Scheme 16 (“Method P”),wherein R¹, R^(2b), R^(3a)R^(3b), R^(4a), R^(4b), R⁹, R¹⁰, Q, m¹ and m²are as defined herein above. As shown in General Reaction Scheme 16,compound O-2 is chlorinated using N-chlorosuccinimide to yield P-1.Reaction of P-1 with diethyl-2-(ethoxymethylene)malonate yields P-2. P-2is then cyclized by heating in an appropriate high-boiling solvent (e.g.Ph₂O) to yield the quinolone, P-3. P-3 is chlorinated under appropriateconditions (e.g., SOCl₂, POCl₃/PCl₅ or POCl₃) to yield thechloroquinolone, P-4. Reaction of P-4 with an appropriately protectedheterocycle under basic conditions yields P-5. Appropriate protectinggroups include butyloxycarbonyl (BOC) as depicted in General reactionScheme 1, as well as other protecting groups known in the art.Saponification of P-5 followed by amidation yields P-6 and P-7,respectively. Suzuki reaction of P-7 with an appropriate reagent toinstall the R¹ moiety results in P-8. Deprotection of P-8 followed byacylation with an acid chloride (or sulfonyl chloride) or acid andappropriate activating reagents yields P-9. Reaction of P-9 in thepresence of acid yielded P-10.

Embodiments of the compound of structure (I) (e.g., compound Q-2) can beprepared according to General Reaction Scheme 16 (“Method Q”), whereinR¹, R^(2b), R^(3a)R^(3b), R^(4a), R^(4b), R⁹, R¹⁰, Q, m¹ and m² are asdefined herein above. As shown in General Reaction Scheme 17,deprotection of compound O-9 followed by acylation with an acid chloride(or sulfonyl chloride) or acid and appropriate activating reagentsyields Q-1. Suzuki reaction of Q-1 with an appropriate reagent toinstall the R¹ moiety results in Q-2.

Additional General synthetic methods are provided in the Examples. Itwill be apparrent to one of ordinary skill in the art that all compoundsof structure (I) can be prepared according to one or more of the methodsdescribed herein or otherwise known in the art. It will also be apparentthat in some instances it will be necessary to use a differenrentlysubstituted starting material and/or protecting groups to arrive at thedesired compound when following the general procedures described herein.Various substituents may also be added at various points in thesynthetic scheme to prepare the desired compound.

Further, one skilled in the art will recognize that certainmodifications to the above schemes and those provided in the examplesare possible to prepare different embodiments of compounds of structure(I). For example, for ease of illustration, most of the generalprocedures depict preparation of compounds of structure (I) wherein L¹is a bond. However, one of ordinary skill in the art will readilyrecognize that compounds wherein L¹ is NR⁷ can be prepared bysubstituting a heterocycle having the following structure (see e.g.,Method C):

where R is H, a protecting group or C₁-C₆alkyl.

Pharmaceutical Compositions

Other embodiments are directed to pharmaceutical compositions. Thepharmaceutical composition comprises any one (or more) of the foregoingcompounds and a pharmaceutically acceptable carrier. In someembodiments, the pharmaceutical composition is formulated for oraladministration. In other embodiments, the pharmaceutical composition isformulated for injection. In still more embodiments, the pharmaceuticalcompositions comprise a compound as disclosed herein and an additionaltherapeutic agent (e.g., anticancer agent). Non-limiting examples ofsuch therapeutic agents are described herein below.

Suitable routes of administration include, but are not limited to, oral,intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary,transmucosal, transdermal, vaginal, otic, nasal, and topicaladministration. In addition, by way of example only, parenteral deliveryincludes intramuscular, subcutaneous, intravenous, intramedullaryinjections, as well as intrathecal, direct intraventricular,intraperitoneal, intralymphatic, and intranasal injections.

In certain embodiments, a compound as described herein is administeredin a local rather than systemic manner, for example, via injection ofthe compound directly into an organ, often in a depot preparation orsustained release formulation. In specific embodiments, long actingformulations are administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection.Furthermore, in other embodiments, the drug is delivered in a targeteddrug delivery system, for example, in a liposome coated withorgan-specific antibody. In such embodiments, the liposomes are targetedto and taken up selectively by the organ. In yet other embodiments, thecompound as described herein is provided in the form of a rapid releaseformulation, in the form of an extended release formulation, or in theform of an intermediate release formulation. In yet other embodiments,the compound described herein is administered topically.

The compounds according to the invention are effective over a widedosage range. For example, in the treatment of adult humans, dosagesfrom 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, andfrom 5 to 40 mg per day are examples of dosages that are used in someembodiments. An exemplary dosage is 10 to 30 mg per day. The exactdosage will depend upon the route of administration, the form in whichthe compound is administered, the subject to be treated, the body weightof the subject to be treated, and the preference and experience of theattending physician.

In some embodiments, a compound of the invention is administered in asingle dose. Typically, such administration will be by injection, e.g.,intravenous injection, in order to introduce the agent quickly. However,other routes are used as appropriate. A single dose of a compound of theinvention may also be used for treatment of an acute condition.

In some embodiments, a compound of the invention is administered inmultiple doses. In some embodiments, dosing is about once, twice, threetimes, four times, five times, six times, or more than six times perday. In other embodiments, dosing is about once a month, once every twoweeks, once a week, or once every other day. In another embodiment acompound of the invention and another agent are administered togetherabout once per day to about 6 times per day. In another embodiment theadministration of a compound of the invention and an agent continues forless than about 7 days. In yet another embodiment the administrationcontinues for more than about 6, 10, 14, 28 days, two months, sixmonths, or one year. In some cases, continuous dosing is achieved andmaintained as long as necessary.

Administration of the compounds of the invention may continue as long asnecessary. In some embodiments, a compound of the invention isadministered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In someembodiments, a compound of the invention is administered for less than28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound ofthe invention is administered chronically on an ongoing basis, e.g., forthe treatment of chronic effects.

In some embodiments, the compounds of the invention are administered indosages. It is known in the art that due to intersubject variability incompound pharmacokinetics, individualization of dosing regimen isnecessary for optimal therapy. Dosing for a compound of the inventionmay be found by routine experimentation in light of the instantdisclosure.

In some embodiments, the compounds described herein are formulated intopharmaceutical compositions. In specific embodiments, pharmaceuticalcompositions are formulated in a conventional manner using one or morephysiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen. Any pharmaceuticallyacceptable techniques, carriers, and excipients are used as suitable toformulate the pharmaceutical compositions described herein: Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins 1999).

Provided herein are pharmaceutical compositions comprising a compound ofstructure (I) and a pharmaceutically acceptable diluent(s),excipient(s), or carrier(s). In certain embodiments, the compoundsdescribed are administered as pharmaceutical compositions in whichcompounds of structure (I) are mixed with other active ingredients, asin combination therapy. Encompassed herein are all combinations ofactives set forth in the combination therapies section below andthroughout this disclosure. In specific embodiments, the pharmaceuticalcompositions include one or more compounds of structure (I).

A pharmaceutical composition, as used herein, refers to a mixture of acompound of structure (I) with other chemical components, such ascarriers, stabilizers, diluents, dispersing agents, suspending agents,thickening agents, and/or excipients. In certain embodiments, thepharmaceutical composition facilitates administration of the compound toan organism. In some embodiments, practicing the methods of treatment oruse provided herein, therapeutically effective amounts of compounds ofstructure (I) provided herein are administered in a pharmaceuticalcomposition to a mammal having a disease, disorder or medical conditionto be treated. In specific embodiments, the mammal is a human. Incertain embodiments, therapeutically effective amounts vary depending onthe severity of the disease, the age and relative health of the subject,the potency of the compound used and other factors. The compoundsdescribed herein are used singly or in combination with one or moretherapeutic agents as components of mixtures.

In one embodiment, one or more compounds of structure (I) is formulatedin an aqueous solutions. In specific embodiments, the aqueous solutionis selected from, by way of example only, a physiologically compatiblebuffer, such as Hank's solution, Ringer's solution, or physiologicalsaline buffer. In other embodiments, one or more compound of structure(I) is/are formulated for transmucosal administration. In specificembodiments, transmucosal formulations include penetrants that areappropriate to the barrier to be permeated. In still other embodimentswherein the compounds described herein are formulated for otherparenteral injections, appropriate formulations include aqueous ornonaqueous solutions. In specific embodiments, such solutions includephysiologically compatible buffers and/or excipients.

In another embodiment, compounds described herein are formulated fororal administration. Compounds described herein are formulated bycombining the active compounds with, e.g., pharmaceutically acceptablecarriers or excipients. In various embodiments, the compounds describedherein are formulated in oral dosage forms that include, by way ofexample only, tablets, powders, pills, dragees, capsules, liquids, gels,syrups, elixirs, slurries, suspensions and the like.

In certain embodiments, pharmaceutical preparations for oral use areobtained by mixing one or more solid excipient with one or more of thecompounds described herein, optionally grinding the resulting mixture,and processing the mixture of granules, after adding suitableauxiliaries, if desired, to obtain tablets or dragee cores. Suitableexcipients are, in particular, fillers such as sugars, includinglactose, sucrose, mannitol, or sorbitol; cellulose preparations such as:for example, maize starch, wheat starch, rice starch, potato starch,gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Inspecific embodiments, disintegrating agents are optionally added.Disintegrating agents include, by way of example only, cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate.

In one embodiment, dosage forms, such as dragee cores and tablets, areprovided with one or more suitable coating. In specific embodiments,concentrated sugar solutions are used for coating the dosage form. Thesugar solutions, optionally contain additional components, such as byway of example only, gum arabic, talc, polyvinylpyrrolidone, carbopolgel, polyethylene glycol, and/or titanium dioxide, lacquer solutions,and suitable organic solvents or solvent mixtures. Dyestuffs and/orpigments are also optionally added to the coatings for identificationpurposes. Additionally, the dyestuffs and/or pigments are optionallyutilized to characterize different combinations of active compounddoses.

In certain embodiments, therapeutically effective amounts of at leastone of the compounds described herein are formulated into other oraldosage forms. Oral dosage forms include push-fit capsules made ofgelatin, as well as soft, sealed capsules made of gelatin and aplasticizer, such as glycerol or sorbitol. In specific embodiments,push-fit capsules contain the active ingredients in admixture with oneor more filler. Fillers include, by way of example only, lactose,binders such as starches, and/or lubricants such as talc or magnesiumstearate and, optionally, stabilizers. In other embodiments, softcapsules, contain one or more active compound that is dissolved orsuspended in a suitable liquid. Suitable liquids include, by way ofexample only, one or more fatty oil, liquid paraffin, or liquidpolyethylene glycol. In addition, stabilizers are optionally added.

In other embodiments, therapeutically effective amounts of at least oneof the compounds described herein are formulated for buccal orsublingual administration. Formulations suitable for buccal orsublingual administration include, by way of example only, tablets,lozenges, or gels. In still other embodiments, the compounds describedherein are formulated for parental injection, including formulationssuitable for bolus injection or continuous infusion. In specificembodiments, formulations for injection are presented in unit dosageform (e.g., in ampoules) or in multi-dose containers. Preservatives are,optionally, added to the injection formulations. In still otherembodiments, the pharmaceutical compositions are formulated in a formsuitable for parenteral injection as sterile suspensions, solutions oremulsions in oily or aqueous vehicles. Parenteral injection formulationsoptionally contain formulatory agents such as suspending, stabilizingand/or dispersing agents. In specific embodiments, pharmaceuticalformulations for parenteral administration include aqueous solutions ofthe active compounds in water-soluble form. In additional embodiments,suspensions of the active compounds (e.g., compounds of structure (I))are prepared as appropriate oily injection suspensions. Suitablelipophilic solvents or vehicles for use in the pharmaceuticalcompositions described herein include, by way of example only, fattyoils such as sesame oil, or synthetic fatty acid esters, such as ethyloleate or triglycerides, or liposomes. In certain specific embodiments,aqueous injection suspensions contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension contains suitablestabilizers or agents which increase the solubility of the compounds toallow for the preparation of highly concentrated solutions.Alternatively, in other embodiments, the active ingredient is in powderform for constitution with a suitable vehicle, e.g., sterilepyrogen-free water, before use.

In still other embodiments, the compounds of structure (I) areadministered topically. The compounds described herein are formulatedinto a variety of topically administrable compositions, such assolutions, suspensions, lotions, gels, pastes, medicated sticks, balms,creams or ointments. Such pharmaceutical compositions optionally containsolubilizers, stabilizers, tonicity enhancing agents, buffers andpreservatives.

In yet other embodiments, the compounds of structure (I) are formulatedfor transdermal administration. In specific embodiments, transdermalformulations employ transdermal delivery devices and transdermaldelivery patches and can be lipophilic emulsions or buffered, aqueoussolutions, dissolved and/or dispersed in a polymer or an adhesive. Invarious embodiments, such patches are constructed for continuous,pulsatile, or on demand delivery of pharmaceutical agents. In additionalembodiments, the transdermal delivery of the compounds of structure (I)is accomplished by means of iontophoretic patches and the like. Incertain embodiments, transdermal patches provide controlled delivery ofthe compounds of structure (I). In specific embodiments, the rate ofabsorption is slowed by using rate-controlling membranes or by trappingthe compound within a polymer matrix or gel. In alternative embodiments,absorption enhancers are used to increase absorption. Absorptionenhancers or carriers include absorbable pharmaceutically acceptablesolvents that assist passage through the skin. For example, in oneembodiment, transdermal devices are in the form of a bandage comprisinga backing member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundto the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.

In other embodiments, the compounds of structure (I) are formulated foradministration by inhalation. Various forms suitable for administrationby inhalation include, but are not limited to, aerosols, mists orpowders. Pharmaceutical compositions of any of compound of structure (I)are conveniently delivered in the form of an aerosol spray presentationfrom pressurized packs or a nebuliser, with the use of a suitablepropellant (e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas). Inspecific embodiments, the dosage unit of a pressurized aerosol isdetermined by providing a valve to deliver a metered amount. In certainembodiments, capsules and cartridges of, such as, by way of exampleonly, gelatin for use in an inhaler or insufflator are formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

In still other embodiments, the compounds of structure (I) areformulated in rectal compositions such as enemas, rectal gels, rectalfoams, rectal aerosols, suppositories, jelly suppositories, or retentionenemas, containing conventional suppository bases such as cocoa butteror other glycerides, as well as synthetic polymers such aspolyvinylpyrrolidone, PEG, and the like. In suppository forms of thecompositions, a low-melting wax such as, but not limited to, a mixtureof fatty acid glycerides, optionally in combination with cocoa butter isfirst melted.

In certain embodiments, pharmaceutical compositions are formulated inany conventional manner using one or more physiologically acceptablecarriers comprising excipients and auxiliaries which facilitateprocessing of the active compounds into preparations which can be usedpharmaceutically. Proper formulation is dependent upon the route ofadministration chosen. Any pharmaceutically acceptable techniques,carriers, and excipients are optionally used as suitable. Pharmaceuticalcompositions comprising a compound of structure (I) are manufactured ina conventional manner, such as, by way of example only, by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or compression processes.

Pharmaceutical compositions include at least one pharmaceuticallyacceptable carrier, diluent or excipient and at least one compound ofstructure (I), described herein as an active ingredient. The activeingredient is in free-acid or free-base form, or in a pharmaceuticallyacceptable salt form. In addition, the methods and pharmaceuticalcompositions described herein include the use of N-oxides, crystallineforms (also known as polymorphs), as well as active metabolites of thesecompounds having the same type of activity. All tautomers of thecompounds described herein are included within the scope of thecompounds presented herein. Additionally, the compounds described hereinencompass unsolvated as well as solvated forms with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. The solvatedforms of the compounds presented herein are also considered to bedisclosed herein. In addition, the pharmaceutical compositionsoptionally include other medicinal or pharmaceutical agents, carriers,adjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressure,buffers, and/or other therapeutically valuable substances.

Methods for the preparation of compositions comprising the compoundsdescribed herein include formulating the compounds with one or moreinert, pharmaceutically acceptable excipients or carriers to form asolid, semi-solid or liquid. Solid compositions include, but are notlimited to, powders, tablets, dispersible granules, capsules, cachets,and suppositories. Liquid compositions include solutions in which acompound is dissolved, emulsions comprising a compound, or a solutioncontaining liposomes, micelles, or nanoparticles comprising a compoundas disclosed herein. Semi-solid compositions include, but are notlimited to, gels, suspensions and creams. The form of the pharmaceuticalcompositions described herein include liquid solutions or suspensions,solid forms suitable for solution or suspension in a liquid prior touse, or as emulsions. These compositions also optionally contain minoramounts of nontoxic, auxiliary substances, such as wetting oremulsifying agents, pH buffering agents, and so forth.

In some embodiments, pharmaceutical composition comprising at least onecompound of structure (I) illustratively takes the form of a liquidwhere the agents are present in solution, in suspension or both.Typically when the composition is administered as a solution orsuspension a first portion of the agent is present in solution and asecond portion of the agent is present in particulate form, insuspension in a liquid matrix. In some embodiments, a liquid compositionincludes a gel formulation. In other embodiments, the liquid compositionis aqueous.

In certain embodiments, useful aqueous suspensions contain one or morepolymers as suspending agents. Useful polymers include water-solublepolymers such as cellulosic polymers, e.g., hydroxypropylmethylcellulose, and water-insoluble polymers such as cross-linkedcarboxyl-containing polymers. Certain pharmaceutical compositionsdescribed herein comprise a mucoadhesive polymer, selected for examplefrom carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

Useful pharmaceutical compositions also, optionally, includesolubilizing agents to aid in the solubility of a compound of structure(I). The term “solubilizing agent” generally includes agents that resultin formation of a micellar solution or a true solution of the agent.Certain acceptable nonionic surfactants, for example polysorbate 80, areuseful as solubilizing agents, as can ophthalmically acceptable glycols,polyglycols, e.g., polyethylene glycol 400, and glycol ethers.

Furthermore, useful pharmaceutical compositions optionally include oneor more pH adjusting agents or buffering agents, including acids such asacetic, boric, citric, lactic, phosphoric and hydrochloric acids; basessuch as sodium hydroxide, sodium phosphate, sodium borate, sodiumcitrate, sodium acetate, sodium lactate andtris-hydroxymethylaminomethane; and buffers such as citrate/dextrose,sodium bicarbonate and ammonium chloride. Such acids, bases and buffersare included in an amount required to maintain pH of the composition inan acceptable range.

Additionally, useful compositions also, optionally, include one or moresalts in an amount required to bring osmolality of the composition intoan acceptable range. Such salts include those having sodium, potassiumor ammonium cations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable saltsinclude sodium chloride, potassium chloride, sodium thiosulfate, sodiumbisulfite and ammonium sulfate.

Other useful pharmaceutical compositions optionally include one or morepreservatives to inhibit microbial activity. Suitable preservativesinclude mercury-containing substances such as merfen and thiomersal;stabilized chlorine dioxide; and quaternary ammonium compounds such asbenzalkonium chloride, cetyltrimethylammonium bromide andcetylpyridinium chloride.

Still other useful compositions include one or more surfactants toenhance physical stability or for other purposes. Suitable nonionicsurfactants include polyoxyethylene fatty acid glycerides and vegetableoils, e.g., polyoxyethylene (60) hydrogenated castor oil; andpolyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10,octoxynol 40.

Still other useful compositions include one or more antioxidants toenhance chemical stability where required. Suitable antioxidantsinclude, by way of example only, ascorbic acid and sodium metabisulfite.

In certain embodiments, aqueous suspension compositions are packaged insingle-dose non-reclosable containers. Alternatively, multiple-dosereclosable containers are used, in which case it is typical to include apreservative in the composition.

In alternative embodiments, other delivery systems for hydrophobicpharmaceutical compounds are employed. Liposomes and emulsions areexamples of delivery vehicles or carriers useful herein. In certainembodiments, organic solvents such as N-methylpyrrolidone are alsoemployed. In additional embodiments, the compounds described herein aredelivered using a sustained-release system, such as semipermeablematrices of solid hydrophobic polymers containing the therapeutic agent.Various sustained-release materials are useful herein. In someembodiments, sustained-release capsules release the compounds for a fewweeks up to over 100 days. Depending on the chemical nature and thebiological stability of the therapeutic reagent, additional strategiesfor protein stabilization are employed.

In certain embodiments, the formulations described herein comprise oneor more antioxidants, metal chelating agents, thiol containing compoundsand/or other general stabilizing agents. Examples of such stabilizingagents, include, but are not limited to: (a) about 0.5% to about 2% w/vglycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% toabout 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e)about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/vpolysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h)arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l)pentosan polysulfate and other heparinoids, (m) divalent cations such asmagnesium and zinc; or (n) combinations thereof.

In some embodiments, the concentration of one or more compounds providedin the pharmaceutical compositions of the present invention is less than100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%,14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%,0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%,0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%,0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%,0.0003%, 0.0002%, or 0.0001% w/w, w/v or v/v.

In some embodiments, the concentration of one or more compounds of theinvention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%,19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%,17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%,14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%,12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%,9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%,6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%,3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%,1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%,0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%,0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%,0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v, or v/v.

In some embodiments, the concentration of one or more compounds of theinvention is in the range from approximately 0.0001% to approximately50%, approximately 0.001% to approximately 40%, approximately 0.01% toapproximately 30%, approximately 0.02% to approximately 29%,approximately 0.03% to approximately 28%, approximately 0.04% toapproximately 27%, approximately 0.05% to approximately 26%,approximately 0.06% to approximately 25%, approximately 0.07% toapproximately 24%, approximately 0.08% to approximately 23%,approximately 0.09% to approximately 22%, approximately 0.1% toapproximately 21%, approximately 0.2% to approximately 20%,approximately 0.3% to approximately 19%, approximately 0.4% toapproximately 18%, approximately 0.5% to approximately 17%,approximately 0.6% to approximately 16%, approximately 0.7% toapproximately 15%, approximately 0.8% to approximately 14%,approximately 0.9% to approximately 12%, approximately 1% toapproximately 10% w/w, w/v or v/v.

In some embodiments, the concentration of one or more compounds of theinvention is in the range from approximately 0.001% to approximately10%, approximately 0.01% to approximately 5%, approximately 0.02% toapproximately 4.5%, approximately 0.03% to approximately 4%,approximately 0.04% to approximately 3.5%, approximately 0.05% toapproximately 3%, approximately 0.06% to approximately 2.5%,approximately 0.07% to approximately 2%, approximately 0.08% toapproximately 1.5%, approximately 0.09% to approximately 1%,approximately 0.1% to approximately 0.9% w/w, w/v or v/v.

In some embodiments, the amount of one or more compounds of theinvention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g,2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g,0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g,0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g,0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g,0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.

In some embodiments, the amount of one or more compounds of theinvention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g,0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g,0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g,0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g,0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g,7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g.

In some embodiments, the amount of one or more compounds of theinvention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

Kits/Articles of Manufacture

For use in the therapeutic applications described herein, kits andarticles of manufacture are also provided. In some embodiments, suchkits comprise a carrier, package, or container that is compartmentalizedto receive one or more containers such as vials, tubes, and the like,each of the container(s) comprising one of the separate elements to beused in a method described herein. Suitable containers include, forexample, bottles, vials, syringes, and test tubes. The containers areformed from a variety of materials such as glass or plastic.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging pharmaceutical products includethose found in, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252.Examples of pharmaceutical packaging materials include, but are notlimited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials,containers, syringes, bottles, and any packaging material suitable for aselected formulation and intended mode of administration and treatment.For example, the container(s) includes one or more compounds describedherein, optionally in a composition or in combination with another agentas disclosed herein. The container(s) optionally have a sterile accessport (for example the container is an intravenous solution bag or a vialhaving a stopper pierceable by a hypodermic injection needle). Such kitsoptionally comprising a compound with an identifying description orlabel or instructions relating to its use in the methods describedherein.

For example, a kit typically includes one or more additional containers,each with one or more of various materials (such as reagents, optionallyin concentrated form, and/or devices) desirable from a commercial anduser standpoint for use of a compound described herein. Non-limitingexamples of such materials include, but not limited to, buffers,diluents, filters, needles, syringes; carrier, package, container, vialand/or tube labels listing contents and/or instructions for use, andpackage inserts with instructions for use. A set of instructions willalso typically be included. A label is optionally on or associated withthe container. For example, a label is on a container when letters,numbers or other characters forming the label are attached, molded oretched into the container itself, a label is associated with a containerwhen it is present within a receptacle or carrier that also holds thecontainer, e.g., as a package insert. In addition, a label is used toindicate that the contents are to be used for a specific therapeuticapplication. In addition, the label indicates directions for use of thecontents, such as in the methods described herein. In certainembodiments, the pharmaceutical compositions is presented in a pack ordispenser device which contains one or more unit dosage forms containinga compound provided herein. The pack for example contains metal orplastic foil, such as a blister pack. Or, the pack or dispenser deviceis accompanied by instructions for administration. Or, the pack ordispenser is accompanied with a notice associated with the container inform prescribed by a governmental agency regulating the manufacture,use, or sale of pharmaceuticals, which notice is reflective of approvalby the agency of the form of the drug for human or veterinaryadministration. Such notice, for example, is the labeling approved bythe U.S. Food and Drug Administration for prescription drugs, or theapproved product insert. In some embodiments, compositions containing acompound provided herein formulated in a compatible pharmaceuticalcarrier are prepared, placed in an appropriate container, and labeledfor treatment of an indicated condition.

Methods

The present invention provides a method of inhibiting RAS-mediated cellsignaling comprising contacting a cell with an effective amount of oneor more compounds disclosed herein. Inhibition of RAS-mediated signaltransduction can be assessed and demonstrated by a wide variety of waysknown in the art. Non-limiting examples include a showing of (a) adecrease in GTPase activity of RAS; (b) a decrease in GTP bindingaffinity or an increase in GDP binding affinity; (c) an increase in Koff of GTP or a decrease in K off of GDP; (d) a decrease in the levelsof signaling transduction molecules downstream in the RAS pathway, suchas a decrease in pMEK level; and/or (e) a decrease in binding of RAScomplex to downstream signaling molecules including but not limited toRaf Kits and commercially available assays can be utilized fordetermining one or more of the above.

The invention also provides methods of using the compounds orpharmaceutical compositions of the present invention to treat diseaseconditions, including but not limited to conditions implicated by G12CKRAS, HRAS or NRAS mutation, G12C HRAS mutation and/or G12C NRASmutation (e.g., cancer).

In some embodiments, a method for treatment of cancer is provided, themethod comprising administering an effective amount of any of theforegoing pharmaceutical compositions comprising a compound of structure(I) to a subject in need thereof. In some embodiments, the cancer ismediated by a KRAS, HRAS or NRAS G12C mutation. In other embodiments,the cancer is pancreatic cancer, colon cancer, MYH associated polyposis,colorectal cancer or lung cancer.

In some embodiments the invention provides method of treating a disorderin a subject in need thereof, wherein the said method comprisesdetermining if the subject has a KRAS, HRAS or NRAS G12C mutation and ifthe subject is determined to have the KRAS, HRAS or NRAS G12C mutation,then administering to the subject a therapeutically effective dose of atleast one compound of structure (I) or a pharmaceutically acceptablesalt, ester, prodrug, tautomer, solvate, hydrate or derivative thereof.

The disclosed compounds strongly inhibit anchorage-independent cellgrowth and therefore have the potential to inhibit tumor metastasis.Accordingly, in another embodiment the disclosure provides a method forinhibiting tumor metastasis, the method comprising administering aneffective amount a pharmaceutical composition of comprising any of thecompounds disclosed herein and a pharmaceutically acceptable carrier toa subject in need thereof.

KRAS, HRAS or NRAS G12C mutations have also been identified inhematological malignancies (e.g., cancers that affect blood, bone marrowand/or lymph nodes). Accordingly, certain embodiments are directed toadministration of a disclosed compounds (e.g., in the form of apharmaceutical composition) to a patient in need of treatment of ahematological malignancy. Such malignancies include, but are not limitedto leukemias and lymphomas. For example, the presently disclosedcompounds can be used for treatment of diseases such as Acutelymphoblastic leukemia (ALL), Acute myelogenous leukemia (AML), Chroniclymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Chronicmyelogenous leukemia (CML), Acute monocytic leukemia (AMoL) and/or otherleukemias. In other embodiments, the compounds are useful for treatmentof lymphomas such as all subtypes of Hodgkins lymphoma or non-Hodgkinslymphoma.

Determining whether a tumor or cancer comprises a G12C KRAS, HRAS orNRAS mutation can be undertaken by assessing the nucleotide sequenceencoding the KRAS, HRAS or NRAS protein, by assessing the amino acidsequence of the KRAS, HRAS or NRAS protein, or by assessing thecharacteristics of a putative KRAS, HRAS or NRAS mutant protein. Thesequence of wild-type human KRAS, HRAS or NRAS is known in the art,(e.g. Accession No. NP203524).

Methods for detecting a mutation in a KRAS, HRAS or NRAS nucleotidesequence are known by those of skill in the art. These methods include,but are not limited to, polymeRASe chain reaction-restriction fragmentlength polymorphism (PCR-RFLP) assays, polymeRASe chain reaction-singlestrand conformation polymorphism (PCR-SSCP) assays, real-time PCRassays, PCR sequencing, mutant allele-specific PCR amplification (MASA)assays, direct sequencing, primer extension reactions, electrophoresis,oligonucleotide ligation assays, hybridization assays, TaqMan assays,SNP genotyping assays, high resolution melting assays and microarrayanalyses. In some embodiments, samples are evaluated for G12C KRAS, HRASor NRAS mutations by real-time PCR. In real-time PCR, fluorescent probesspecific for the KRAS, HRAS or NRAS G12C mutation are used. When amutation is present, the probe binds and fluorescence is detected. Insome embodiments, the KRAS, HRAS or NRAS G12C mutation is identifiedusing a direct sequencing method of specific regions (e.g., exon 2and/or exon 3) in the KRAS, HRAS or NRAS gene. This technique willidentify all possible mutations in the region sequenced.

Methods for detecting a mutation in a KRAS, HRAS or NRAS protein areknown by those of skill in the art. These methods include, but are notlimited to, detection of a KRAS, HRAS or NRAS mutant using a bindingagent (e.g., an antibody) specific for the mutant protein, proteinelectrophoresis and Western blotting, and direct peptide sequencing.

Methods for determining whether a tumor or cancer comprises a G12C KRAS,HRAS or NRAS mutation can use a variety of samples. In some embodiments,the sample is taken from a subject having a tumor or cancer. In someembodiments, the sample is taken from a subject having a cancer ortumor. In some embodiments, the sample is a fresh tumor/cancer sample.In some embodiments, the sample is a frozen tumor/cancer sample. In someembodiments, the sample is a formalin-fixed paraffin-embedded sample. Insome embodiments, the sample is processed to a cell lysate. In someembodiments, the sample is processed to DNA or RNA.

The invention also relates to a method of treating a hyperproliferativedisorder in a mammal that comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrateor derivative thereof. In some embodiments, said method relates to thetreatment of cancer such as acute myeloid leukemia, cancer inadolescents, adrenocortical carcinoma childhood, AIDS-related cancers(e.g. Lymphoma and Kaposi's Sarcoma), anal cancer, appendix cancer,astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer,bladder cancer, bone cancer, brain stem glioma, brain tumor, breastcancer, bronchial tumors, burkitt lymphoma, carcinoid tumor, atypicalteratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervicalcancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocyticleukemia (CLL), chronic myelogenous leukemia (CML), chronicmyleoproliferative disorders, colon cancer, colorectal cancer,craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductalcarcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrialcancer, ependymoma, esophageal cancer, esthesioneuroblastoma, ewingsarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eyecancer, fibrous histiocytoma of bone, gall bladder cancer, gastriccancer, gastrointestinal carcinoid tumor, gastrointestinal stromaltumors (GIST), germ cell tumor, gestational trophoblastic tumor, hairycell leukemia, head and neck cancer, heart cancer, liver cancer, hodgkinlymphoma, hypopharyngeal cancer, intraocular melanoma, islet celltumors, pancreatic neuroendocrine tumors, kidney cancer, laryngealcancer, lip and oral cavity cancer, liver cancer, lobular carcinoma insitu (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer withoccult primary, midline tract carcinoma, mouth cancer multiple endocrineneoplasia syndromes, multiple myeloma/plasma cell neoplasm, mycosisfungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferativeneoplasms, multiple myeloma, merkel cell carcinoma, malignantmesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma,nasal cavity and paranasal sinus cancer, nasopharyngeal cancer,neuroblastoma, non-hodgkin lymphoma, non-small cell lung cancer (NSCLC),oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovariancancer, pancreatic cancer, papillomatosis, paraganglioma, paranasalsinus and nasal cavity cancer, parathyroid cancer, penile cancer,pharyngeal cancer, pleuropulmonary blastoma, primary central nervoussystem (CNS) lymphoma, prostate cancer, rectal cancer, transitional cellcancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skincancer, stomach (gastric) cancer, small cell lung cancer, smallintestine cancer, soft tissue sarcoma, T-Cell lymphoma, testicularcancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer,transitional cell cancer of the renal pelvis and ureter, trophoblastictumor, unusual cancers of childhood, urethral cancer, uterine sarcoma,vaginal cancer, vulvar cancer, or Viral-Induced cancer. In someembodiments, said method relates to the treatment of a non-canceroushyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e. g., benign prostatichypertrophy (BPH)).

In certain particular embodiments, the invention relates to methods fortreatment of lung cancers, the methods comprise administering aneffective amount of any of the above described compound (or apharmaceutical composition comprising the same) to a subject in needthereof. In certain embodiments the lung cancer is a non-small cell lungcarcinoma (NSCLC), for example adenocarcinoma, squamous-cell lungcarcinoma or large-cell lung carcinoma. In other embodiments, the lungcancer is a small cell lung carcinoma. Other lung cancers treatable withthe disclosed compounds include, but are not limited to, glandulartumors, carcinoid tumors and undifferentiated carcinomas.

Subjects that can be treated with compounds of the invention, orpharmaceutically acceptable salt, ester, prodrug, solvate, tautomer,hydrate or derivative of said compounds, according to the methods ofthis invention include, for example, subjects that have been diagnosedas having acute myeloid leukemia, acute myeloid leukemia, cancer inadolescents, adrenocortical carcinoma childhood, AIDS-related cancers(e.g. Lymphoma and Kaposi's Sarcoma), anal cancer, appendix cancer,astrocytomas, atypical teratoid, basal cell carcinoma, bile duct cancer,bladder cancer, bone cancer, brain stem glioma, brain tumor, breastcancer, bronchial tumors, burkitt lymphoma, carcinoid tumor, atypicalteratoid, embryonal tumors, germ cell tumor, primary lymphoma, cervicalcancer, childhood cancers, chordoma, cardiac tumors, chronic lymphocyticleukemia (CLL), chronic myelogenous leukemia (CML), chronicmyleoproliferative disorders, colon cancer, colorectal cancer,craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductalcarcinoma in situ (DCIS), embryonal tumors, CNS cancer, endometrialcancer, ependymoma, esophageal cancer, esthesioneuroblastoma, ewingsarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eyecancer, fibrous histiocytoma of bone, gall bladder cancer, gastriccancer, gastrointestinal carcinoid tumor, gastrointestinal stromaltumors (GIST), germ cell tumor, gestational trophoblastic tumor, hairycell leukemia, head and neck cancer, heart cancer, liver cancer, hodgkinlymphoma, hypopharyngeal cancer, intraocular melanoma, islet celltumors, pancreatic neuroendocrine tumors, kidney cancer, laryngealcancer, lip and oral cavity cancer, liver cancer, lobular carcinoma insitu (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer withoccult primary, midline tract carcinoma, mouth cancer multiple endocrineneoplasia syndromes, multiple myeloma/plasma cell neoplasm, mycosisfungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferativeneoplasms, multiple myeloma, merkel cell carcinoma, malignantmesothelioma, malignant fibrous histiocytoma of bone and osteosarcoma,nasal cavity and paranasal sinus cancer, nasopharyngeal cancer,neuroblastoma, non-hodgkin lymphoma, non-small cell lung cancer (NSCLC),oral cancer, lip and oral cavity cancer, oropharyngeal cancer, ovariancancer, pancreatic cancer, papillomatosis, paraganglioma, paranasalsinus and nasal cavity cancer, parathyroid cancer, penile cancer,pharyngeal cancer, pleuropulmonary blastoma, primary central nervoussystem (CNS) lymphoma, prostate cancer, rectal cancer, transitional cellcancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skincancer, stomach (gastric) cancer, small cell lung cancer, smallintestine cancer, soft tissue sarcoma, T-Cell lymphoma, testicularcancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer,transitional cell cancer of the renal pelvis and ureter, trophoblastictumor, unusual cancers of childhood, urethral cancer, uterine sarcoma,vaginal cancer, vulvar cancer, or Viral-Induced cancer. In someembodiments subjects that are treated with the compounds of theinvention include subjects that have been diagnosed as having anon-cancerous hyperproliferative disorder such as benign hyperplasia ofthe skin (e. g., psoriasis), restenosis, or prostate (e. g., benignprostatic hypertrophy (BPH)).

The invention further provides methods of modulating a G12C Mutant KRAS,HRAS or NRAS protein activity by contacting the protein with aneffective amount of a compound of the invention. Modulation can beinhibiting or activating protein activity. In some embodiments, theinvention provides methods of inhibiting protein activity by contactingthe G12C Mutant KRAS, HRAS or NRAS protein with an effective amount of acompound of the invention in solution. In some embodiments, theinvention provides methods of inhibiting the G12C Mutant KRAS, HRAS orNRAS protein activity by contacting a cell, tissue, organ that expressthe protein of interest. In some embodiments, the invention providesmethods of inhibiting protein activity in subject including but notlimited to rodents and mammal (e.g., human) by administering into thesubject an effective amount of a compound of the invention. In someembodiments, the percentage modulation exceeds 25%, 30%, 40%, 50%, 60%,70%, 80%, or 90%. In some embodiments, the percentage of inhibitingexceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

In some embodiments, the invention provides methods of inhibiting KRAS,HRAS or NRAS G12C activity in a cell by contacting said cell with anamount of a compound of the invention sufficient to inhibit the activityof KRAS, HRAS or NRAS G12C in said cell. In some embodiments, theinvention provides methods of inhibiting KRAS, HRAS or NRAS G12Cactivity in a tissue by contacting said tissue with an amount of acompound of the invention sufficient to inhibit the activity of KRAS,HRAS or NRAS G12C in said tissue. In some embodiments, the inventionprovides methods of inhibiting KRAS, HRAS or NRAS G12C activity in anorganism by contacting said organism with an amount of a compound of theinvention sufficient to inhibit the activity of KRAS, HRAS or NRAS G12Cin said organism. In some embodiments, the invention provides methods ofinhibiting KRAS, HRAS or NRAS G12C activity in an animal by contactingsaid animal with an amount of a compound of the invention sufficient toinhibit the activity of KRAS, HRAS or NRAS G12C in said animal. In someembodiments, the invention provides methods of inhibiting KRAS, HRAS orNRAS G12C activity in a mammal by contacting said mammal with an amountof a compound of the invention sufficient to inhibit the activity ofKRAS, HRAS or NRAS G12C in said mammal. In some embodiments, theinvention provides methods of inhibiting KRAS, HRAS or NRAS G12Cactivity in a human by contacting said human with an amount of acompound of the invention sufficient to inhibit the activity of KRAS,HRAS or NRAS G12C in said human. The present invention provides methodsof treating a disease mediated by KRAS, HRAS or NRAS G12C activity in asubject in need of such treatment.

The present invention also provides methods for combination therapies inwhich an agent known to modulate other pathways, or other components ofthe same pathway, or even overlapping sets of target enzymes are used incombination with a compound of the present invention, or apharmaceutically acceptable salt, ester, prodrug, solvate, tautomer,hydrate or derivative thereof. In one aspect, such therapy includes butis not limited to the combination of one or more compounds of theinvention with chemotherapeutic agents, therapeutic antibodies, andradiation treatment, to provide a synergistic or additive therapeuticeffect.

Many chemotherapeutics are presently known in the art and can be used incombination with the compounds of the invention. In some embodiments,the chemotherapeutic is selected from the group consisting of mitoticinhibitors, alkylating agents, anti-metabolites, intercalatingantibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes,topoisomeRASe inhibitors, biological response modifiers, anti-hormones,angiogenesis inhibitors, and anti-androgens.

Non-limiting examples are chemotherapeutic agents, cytotoxic agents, andnon-peptide small molecules such as Gleevec® (Imatinib Mesylate),Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), andAdriamycin as well as a host of chemotherapeutic agents. Non-limitingexamples of chemotherapeutic agents include alkylating agents such asthiotepa and cyclosphosphamide (CYTOXAN™); alkyl sulfonates such asbusulfan, improsulfan and piposulfan; aziridines such as benzodopa,carboquone, meturedopa, and uredopa; ethylenimines and methylamelaminesincluding altretamine, triethylenemelamine, trietylenephosphoramide,triethylenethiophosphaoramide and trimethylolomelamine; nitrogenmustards such as chlorambucil, chlornaphazine, cholophosphamide,estramustine, ifosfamide, mechlorethamine, mechlorethamine oxidehydrochloride, melphalan, novembichin, phenesterine, prednimustine,trofosfamide, uracil mustard; nitrosureas such as carmustine,chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine,bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin,carzinophilin, Casodex™, chromomycins, dactinomycin, daunorubicin,detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin,esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid,nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine,androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine;bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfomithine; elliptinium acetate; etoglucid; galliumnitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone;mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinicacid; 2-ethylhydrazide; procarbazine; PSK®; razoxane; sizofiran;spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes, e.g.paclitaxel (TAXOL™, Bristol-Myers Squibb Oncology, Princeton, N.J.) anddocetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony, France); retinoicacid; esperamicins; capecitabine; and pharmaceutically acceptable salts,acids or derivatives of any of the above. Also included as suitablechemotherapeutic cell conditioners are anti-hormonal agents that act toregulate or inhibit hormone action on tumors such as anti-estrogensincluding for example tamoxifen, (Nolvadex™), raloxifene, aromataseinhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene,LY 117018, onapristone, and toremifene (Fareston); and anti-androgenssuch as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin;chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate;platinum analogs such as cisplatin and carboplatin; vinblastine;platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone;vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin;aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11);topoisomeRASe inhibitor RFS 2000; difluoromethylornithine (DMFO). Wheredesired, the compounds or pharmaceutical composition of the presentinvention can be used in combination with commonly prescribedanti-cancer drugs such as Herceptin®, Avastin®, Erbitux®, Rituxan®,Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, Abagovomab, Acridinecarboxamide, Adecatumumab, 17-N-Allylamino-17-demethoxygeldanamycin,Alpharadin, Alvocidib, 3-Aminopyridine-2-carboxaldehydethiosemicarbazone, Amonafide, Anthracenedione, Anti-CD22 immunotoxins,Antineoplastic, Antitumorigenic herbs, Apaziquone, Atiprimod,Azathioprine, Belotecan, Bendamustine, BIBW 2992, Biricodar,Brostallicin, Bryostatin, Buthionine sulfoximine, CBV (chemotherapy),Calyculin, cell-cycle nonspecific antineoplastic agents, Dichloroaceticacid, Discodermolide, Elsamitrucin, Enocitabine, Epothilone, Eribulin,Everolimus, Exatecan, Exisulind, Ferruginol, Forodesine, Fosfestrol, ICEchemotherapy regimen, IT-101, Imexon, Imiquimod, Indolocarbazole,Irofulven, Laniquidar, Larotaxel, Lenalidomide, Lucanthone, Lurtotecan,Mafosfamide, Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Ortataxel,PAC-1, Pawpaw, Pixantrone, Proteasome inhibitor, Rebeccamycin,Resiquimod, Rubitecan, SN-38, Salinosporamide A, Sapacitabine, StanfordV, Swainsonine, Talaporfin, Tariquidar, Tegafur-uracil, Temodar,Tesetaxel, Triplatin tetranitrate, Tris(2-chloroethyl)amine,Troxacitabine, Uramustine, Vadimezan, Vinflunine, ZD6126 or Zosuquidar.

This invention further relates to a method for using the compounds orpharmaceutical compositions provided herein, in combination withradiation therapy for inhibiting abnormal cell growth or treating thehyperproliferative disorder in the mammal. Techniques for administeringradiation therapy are known in the art, and these techniques can be usedin the combination therapy described herein. The administration of thecompound of the invention in this combination therapy can be determinedas described herein.

Radiation therapy can be administered through one of several methods, ora combination of methods, including without limitation external-beamtherapy, internal radiation therapy, implant radiation, stereotacticradiosurgery, systemic radiation therapy, radiotherapy and permanent ortemporary interstitial brachytherapy. The term “brachytherapy,” as usedherein, refers to radiation therapy delivered by a spatially confinedradioactive material inserted into the body at or near a tumor or otherproliferative tissue disease site. The term is intended withoutlimitation to include exposure to radioactive isotopes (e.g. At-211,1-131, 1-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, andradioactive isotopes of Lu). Suitable radiation sources for use as acell conditioner of the present invention include both solids andliquids. By way of non-limiting example, the radiation source can be aradionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source,I-125 as a solid source, or other radionuclides that emit photons, betaparticles, gamma radiation, or other therapeutic rays. The radioactivematerial can also be a fluid made from any solution of radionuclide(s),e.g., a solution of I-125 or I-131, or a radioactive fluid can beproduced using a slurry of a suitable fluid containing small particlesof solid radionuclides, such as Au-198, Y-90. Moreover, theradionuclide(s) can be embodied in a gel or radioactive micro spheres.

Without being limited by any theory, the compounds of the presentinvention can render abnormal cells more sensitive to treatment withradiation for purposes of killing and/or inhibiting the growth of suchcells. Accordingly, this invention further relates to a method forsensitizing abnormal cells in a mammal to treatment with radiation whichcomprises administering to the mammal an amount of a compound of thepresent invention or pharmaceutically acceptable salt, ester, prodrug,solvate, hydrate or derivative thereof, which amount is effective issensitizing abnormal cells to treatment with radiation. The amount ofthe compound, salt, or solvate in this method can be determinedaccording to the means for ascertaining effective amounts of suchcompounds described herein.

The compounds or pharmaceutical compositions of the invention can beused in combination with an amount of one or more substances selectedfrom anti-angiogenesis agents, signal transduction inhibitors,antiproliferative agents, glycolysis inhibitors, or autophagyinhibitors.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloproteinase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-11(cyclooxygenase 11) inhibitors, can be used in conjunction with acompound of the invention and pharmaceutical compositions describedherein. Anti-angiogenesis agents include, for example, rapamycin,temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, andbevacizumab. Examples of useful COX-II inhibitors include CELEBREX™(alecoxib), valdecoxib, and rofecoxib. Examples of useful matrixmetalloproteinase inhibitors are described in WO 96/33172 (publishedOct. 24, 1996), WO 96/27583 (published Mar. 7, 1996), European PatentApplication No. 97304971.1 (filed Jul. 8, 1997), European PatentApplication No. 99308617.2 (filed Oct. 29, 1999), WO 98/07697 (publishedFeb. 26, 1998), WO 98/03516 (published Jan. 29, 1998), WO 98/34918(published Aug. 13, 1998), WO 98/34915 (published Aug. 13, 1998), WO98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul. 16,1998), European Patent Publication 606,046 (published Jul. 13, 1994),European Patent Publication 931, 788 (published Jul. 28, 1999), WO90/05719 (published May 31, 1990), WO 99/52910 (published Oct. 21,1999), WO 99/52889 (published Oct. 21, 1999), WO 99/29667 (publishedJun. 17, 1999), PCT International Application No. PCT/IB98/01113 (filedJul. 21, 1998), European Patent Application No. 99302232.1 (filed Mar.25, 1999), Great Britain Patent Application No. 9912961.1 (filed Jun. 3,1999), U.S. Provisional Application No. 60/148,464 (filed Aug. 12,1999), U.S. Pat. No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No.5,861,510 (issued Jan. 19, 1999), and European Patent Publication780,386 (published Jun. 25, 1997), all of which are incorporated hereinin their entireties by reference. Preferred MMP-2 and MMP-9 inhibitorsare those that have little or no activity inhibiting MMP-1. Morepreferred, are those that selectively inhibit MMP-2 and/or AMP-9relative to the other matrix-metalloproteinases (i. e., MAP-1, MMP-3,MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).Some specific examples of MMP inhibitors useful in the invention areAG-3340, RO 32-3555, and RS 13-0830.

Autophagy inhibitors include, but are not limited to chloroquine,3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1,5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid,autophagy-suppressive algal toxins which inhibit protein phosphatases oftype 2A or type 1, analogues of cAMP, and drugs which elevate cAMPlevels such as adenosine, LY204002, N6-mercaptopurine riboside, andvinblastine. In addition, antisense or siRNA that inhibits expression ofproteins including but not limited to ATG5 (which are implicated inautophagy), may also be used.

The invention also relates to a method of and to a pharmaceuticalcomposition for treating a cardiovascular disease in a mammal whichcomprises an amount of a compound of the invention, or apharmaceutically acceptable salt, ester, prodrug, solvate, tautomer,hydrate or derivative thereof, or an isotopically-labeled derivativethereof, and an amount of one or more therapeutic agents use for thetreatment of cardiovascular diseases.

Exemplary agents for use in cardiovascular disease applications areanti-thrombotic agents, e.g., prostacyclin and salicylates, thrombolyticagents, e.g., streptokinase, urokinase, tissue plasminogen activator(TPA) and anisoylated plasminogen-streptokinase activator complex(APSAC), anti-platelets agents, e.g., acetyl-salicylic acid (ASA) andclopidrogel, vasodilating agents, e.g., nitrates, calcium channelblocking drugs, anti-proliferative agents, e.g., colchicine andalkylating agents, intercalating agents, growth modulating factors suchas interleukins, transformation growth factor-beta and congeners ofplatelet derived growth factor, monoclonal antibodies directed againstgrowth factors, anti-inflammatory agents, both steroidal andnon-steroidal, and other agents that can modulate vessel tone, function,arteriosclerosis, and the healing response to vessel or organ injurypost intervention. Antibiotics can also be included in combinations orcoatings comprised by the invention. Moreover, a coating can be used toeffect therapeutic delivery focally within the vessel wall. Byincorporation of the active agent in a swellable polymer, the activeagent will be released upon swelling of the polymer.

In some embodiments, the compounds described herein are formulated oradministered in conjunction with liquid or solid tissue barriers alsoknown as lubricants. Examples of tissue barriers include, but are notlimited to, polysaccharides, polyglycans, seprafilm, interceed andhyaluronic acid.

In some embodiments, medicaments which are administered in conjunctionwith the compounds described herein include any suitable drugs usefullydelivered by inhalation for example, analgesics, e.g. codeine,dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations,e.g. diltiazem; antiallergics, e.g. cromoglycate, ketotifen ornedocromil; anti-infectives, e.g. cephalosporins, penicillins,streptomycin, sulphonamides, tetracyclines or pentamidine;antihistamines, e.g. methapyrilene; anti-inflammatories, e.g.beclomethasone, flunisolide, budesonide, tipredane, triamcinoloneacetonide or fluticasone; antitussives, e.g. noscapine; bronchodilators,e.g. ephedrine, adrenaline, fenoterol, formoterol, isoprenaline,metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol,reproterol, rimiterol, salbutamol, salmeterol, terbutalin, isoetharine,tulobuterol, orciprenaline or(−)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol;diuretics, e.g. amiloride; anticholinergics e.g. ipratropium, atropineor oxitropium; hormones, e.g. cortisone, hydrocortisone or prednisolone;xanthines e.g. aminophylline, choline theophyllinate, lysinetheophyllinate or theophylline; and therapeutic proteins and peptides,e.g. insulin or glucagon. It will be clear to a person skilled in theart that, where appropriate, the medicaments are used in the form ofsalts (e.g. as alkali metal or amine salts or as acid addition salts) oras esters (e.g. lower alkyl esters) or as solvates (e.g. hydrates) tooptimize the activity and/or stability of the medicament.

Other exemplary therapeutic agents useful for a combination therapyinclude but are not limited to agents as described above, radiationtherapy, hormone antagonists, hormones and their releasing factors,thyroid and antithyroid drugs, estrogens and progestins, androgens,adrenocorticotropic hormone; adrenocortical steroids and their syntheticanalogs; inhibitors of the synthesis and actions of adrenocorticalhormones, insulin, oral hypoglycemic agents, and the pharmacology of theendocrine pancreas, agents affecting calcification and bone turnover:calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitaminssuch as water-soluble vitamins, vitamin B complex, ascorbic acid,fat-soluble vitamins, vitamins A, K, and E, growth factors, cytokines,chemokines, muscarinic receptor agonists and antagonists;anticholinesteRASe agents; agents acting at the neuromuscular junctionand/or autonomic ganglia; catecholamines, sympathomimetic drugs, andadrenergic receptor agonists or antagonists; and 5-hydroxytryptamine(5-HT, serotonin) receptor agonists and antagonists.

Therapeutic agents can also include agents for pain and inflammationsuch as histamine and histamine antagonists, bradykinin and bradykininantagonists, 5-hydroxytryptamine (serotonin), lipid substances that aregenerated by biotransformation of the products of the selectivehydrolysis of membrane phospholipids, eicosanoids, prostaglandins,thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatoryagents, analgesic-antipyretic agents, agents that inhibit the synthesisof prostaglandins and thromboxanes, selective inhibitors of theinducible cyclooxygenase, selective inhibitors of the induciblecyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin,cytokines that mediate interactions involved in humoral and cellularimmune responses, lipid-derived autacoids, eicosanoids, β-adrenergicagonists, ipratropium, glucocorticoids, methylxanthines, sodium channelblockers, opioid receptor agonists, calcium channel blockers, membranestabilizers and leukotriene inhibitors.

Additional therapeutic agents contemplated herein include diuretics,vasopressin, agents affecting the renal conservation of water, rennin,angiotensin, agents useful in the treatment of myocardial ischemia,anti-hypertensive agents, angiotensin converting enzyme inhibitors,β-adrenergic receptor antagonists, agents for the treatment ofhypercholesterolemia, and agents for the treatment of dyslipidemia.

Other therapeutic agents contemplated include drugs used for control ofgastric acidity, agents for the treatment of peptic ulcers, agents forthe treatment of gastroesophageal reflux disease, prokinetic agents,antiemetics, agents used in irritable bowel syndrome, agents used fordiarrhea, agents used for constipation, agents used for inflammatorybowel disease, agents used for biliary disease, agents used forpancreatic disease. Therapeutic agents used to treat protozoaninfections, drugs used to treat Malaria, Amebiasis, Giardiasis,Trichomoniasis, Trypanosomiasis, and/or Leishmaniasis, and/or drugs usedin the chemotherapy of helminthiasis. Other therapeutic agents includeantimicrobial agents, sulfonamides, trimethoprim-sulfamethoxazolequinolones, and agents for urinary tract infections, penicillins,cephalosporins, and other, β-lactam antibiotics, an agent comprising anaminoglycoside, protein synthesis inhibitors, drugs used in thechemotherapy of tuberculosis, Mycobacterium avium complex disease, andleprosy, antifungal agents, antiviral agents including nonretroviralagents and antiretroviral agents.

Examples of therapeutic antibodies that can be combined with a compoundof the invention include but are not limited to anti-receptor tyrosinekinase antibodies (cetuximab, panitumumab, tRAStuzumab), anti CD20antibodies (rituximab, tositumomab), and other antibodies such asalemtuzumab, bevacizumab, and gemtuzumab.

Moreover, therapeutic agents used for immunomodulation, such asimmunomodulators, immunosuppressive agents, tolerogens, andimmunostimulants are contemplated by the methods herein. In addition,therapeutic agents acting on the blood and the blood-forming organs,hematopoietic agents, growth factors, minerals, and vitamins,anticoagulant, thrombolytic, and antiplatelet drugs.

For treating renal carcinoma, one may combine a compound of the presentinvention with sorafenib and/or avastin. For treating an endometrialdisorder, one may combine a compound of the present invention withdoxorubincin, taxotere (taxol), and/or cisplatin (carboplatin). Fortreating ovarian cancer, one may combine a compound of the presentinvention with cisplatin (carboplatin), taxotere, doxorubincin,topotecan, and/or tamoxifen. For treating breast cancer, one may combinea compound of the present invention with taxotere (taxol), gemcitabine(capecitabine), tamoxifen, letrozole, tarceva, lapatinib, PD0325901,avastin, herceptin, OSI-906, and/or OSI-930. For treating lung cancer,one may combine a compound of the present invention with taxotere(taxol), gemcitabine, cisplatin, pemetrexed, Tarceva, PD0325901, and/oravastin.

Further therapeutic agents that can be combined with a compound of theinvention are found in Goodman and Gilman's “The Pharmacological Basisof Therapeutics” Tenth Edition edited by Hardman, Limbird and Gilman orthe Physician's Desk Reference, both of which are incorporated herein byreference in their entirety.

The compounds described herein can be used in combination with theagents disclosed herein or other suitable agents, depending on thecondition being treated. Hence, in some embodiments the one or morecompounds of the invention will be co-administered with other agents asdescribed above. When used in combination therapy, the compoundsdescribed herein are administered with the second agent simultaneouslyor separately. This administration in combination can includesimultaneous administration of the two agents in the same dosage form,simultaneous administration in separate dosage forms, and separateadministration. That is, a compound described herein and any of theagents described above can be formulated together in the same dosageform and administered simultaneously. Alternatively, a compound of theinvention and any of the agents described above can be simultaneouslyadministered, wherein both the agents are present in separateformulations. In another alternative, a compound of the presentinvention can be administered just followed by and any of the agentsdescribed above, or vice versa. In some embodiments of the separateadministration protocol, a compound of the invention and any of theagents described above are administered a few minutes apart, or a fewhours apart, or a few days apart.

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations. In the following examples, andthroughout the specification and claims, molecules with a single chiralcenter, unless otherwise noted, exist as a racemic mixture. Thosemolecules with two or more chiral centers, unless otherwise noted, existas a racemic mixture of diastereomers. Single enantiomers/diastereomersmay be obtained by methods known to those skilled in the art.

EXAMPLES

The following examples are provided for exemplary purposes. Othercompounds of structure (I) were prepared according to the followinggeneral procedures as indicated in Table 1.

Example 1 Synthesis of1-(4-(7-chloro-6-(2-chlorophenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one(1)

Compound 1 was prepared according to Method A as described below:

Methyl 2-amino-5-(2-chlorophenyl)-4-chlorobenzoate

A mixture of methyl 2-amino-5-bromo-4-chlorobenzoate (1.2 g, 4.54 mmol),2-chlorophenylboronic acid (0.85 g, 5.44 mmol), Na₂CO₃ (1.44 g, 13.61mmol), and Pd(PPh₃)₄ (0.52 g, 0.45 mmol) in 1,4-dioxane (30 mL) andwater (6 mL) was stirred at 75° C. under argon for 16 h. The mixture wasallowed to cool to room temperature (RT), and concentrated in vacuo. Theresidue was purified by flash column chromatography on silica gel (ethylacetate/petroleum=8:1) to afford the desired product (1.22 g, 91% yield)as a yellow solid.

7-Chloro-6-(2-chlorophenyl)quinazolin-4-ol

A mixture of methyl 2-amino-5-(2-chlorophenyl)-4-chlorobenzoate (342 mg,1.16 mmol), CH(OMe)₃ (306 mg, 2.89 mmol), and NH₄OAc (223 mg, 2.89 mmol)in MeOH (1 mL) in a sealed tube was stirred at 130° C. for 4.5 h. Themixture was allowed to cool to RT, and concentrated in vacuo. Theresidue was purified by flash column chromatography on silica geleluting with DCM and MeOH (40:1) to yield the desired product (277 mg,82% yield) as a white solid. ESI-MS m/z: 289.2 [M−H]⁻.

4,7-Dichloro-6-(2-chlorophenyl)quinazoline

A mixture of 7-chloro-6-(2-chlorophenyl)quinazolin-4-ol (277 mg, 0.95mmol), PCl₅ (397 mg, 1.90 mmol) and POCl₃ (16 mL) was stirred at refluxfor 20 h. The mixture was allowed to cool to RT, and then concentratedin vacuo to yield the crude product (1.19 g) as a dark oil which wasused directly in next step without further purification.

tert-Butyl-4-(7-chloro-6-(2-chlorophenyl)quinazolin-4-yl)piperazine-1-carboxylate

The above obtained crude 4,7-dichloro-6-(2-chlorophenyl)quinazoline(1.19 g) was added to the mixture of tert-butyl piperazine-1-carboxylate(5 g, 26.9 mmol) and Et₃N (7.76 g, 76.8 mmol) in DCM (200 mL) at 0° C.and the resulting mixture was stirred at the same temperature for 1 h.The mixture was poured into water (500 mL) and brine (100 mL), and thendichloromethane (DCM) (200 mL) was added. The mixture was filteredthrough filter paper. The organic layer was separated, dried over Na₂SO₄and concentrated in vacuo. The residue was purified by flash columnchromatography on silica gel eluting with DCM and MeOH (30:1) to yieldthe desired product (184 mg, 42% yield, 2 steps) as a light yellow oil.ESI-MS m/z: 459.3 [M+H]⁺.

1-(4-(7-Chloro-6-(2-chlorophenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

A mixture oftertbutyl-4-(7-chloro-6-(2-chlorophenyl)quinazolin-4-yl)piperazine-1-carboxylate(184 mg, 0.40 mmol) and HCl in MeOH (20 mL) was stirred at RT for 1 h.The mixture was concentrated in vacuo to yield the crude product (176mg) as a yellow solid which was used directly in next step withoutfurther purification.

1-(4-(7-Chloro-6-(2-chlorophenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one(1)

The above obtained crude1-(4-(7-chloro-6-(2-chlorophenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one(17 6 mg) was dissolved in Et₃N (450 mg, 4.45 mmol) and DCM (30 mL) andcooled to 0° C., acryloyl chloride (44 mg, 0.49 mmol) in DCM (50 mL) wasadded to the mixture. The resulting mixture was allowed to warm to RTand stirred at RT for 1.5 h. The reaction mixture was quenched withsaturated NaHCO₃ aqueous solution, and then extracted with ethylacetate. The organic layer was washed with saturated NaHCO₃ solution andbrine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel eluting with DCMand MeOH (30:1) to yield the desired product (82 mg, 50% yield, 2 steps)as a yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ: 8.75 (s, 1H), 8.03 (s,1H), 7.96 (s, 1H), 7.62-7.49 (m, 4H), 6.81 (dd, J=10.4, 16.4 Hz, 1H),6.15 (dd, J=16.4, 2.4 Hz, 1H), 5.71 (dd, J=10.4, 2.0 Hz, 1H), 3.87-3.72(m, 8H). ESI-MS m/z: 413.2 [M+H]⁺.

Example 2 Synthesis of1-(4-(7-chloro-6-phenylquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one(18)

Compound 18 was prepared according to Method B as described below:

6-Bromo-7-chloroquinazolin-4-ol

A mixture of methyl 2-amino-5-bromo-4-chlorobenzoate (1 g, 3.95 mmol)and NH₂CHO (20 mL) was stirred at 200° C. for 3 h. The mixture wasallowed to cool to RT and quenched with water. The solid precipitate wascollected by filtration and dried in vacuo to yield the desired product(669 mg, 66% yield) as a brown solid.

6-Bromo-4,7-dichloroquinazoline

A mixture of 6-bromo-7-chloroquinazolin-4-ol (669 mg, 2.59 mmol), PCl₅(1.6 g, 7.78 mmol) and POCl₃ (15 mL) was stirred at reflux for 16 h. Themixture was allowed to cool to RT and then concentrated in vacuo toyield the desired product as a dark oil which was used directly in nextstep without further purification.

tert-Butyl 4-(6-bromo-7-chloroquinazolin-4-yl)piperazine-1-carboxylate

The above obtained crude 6-bromo-4,7-dichloroquinazoline was added tothe mixture of tert-butyl piperazine-1-carboxylate (4.82 g, 25.9 mmol)and Et₃N (2.62 g, 25.9 mmol) in DCM (70 mL). The resulting mixture wasstirred at RT for 2 h and then was quenched with saturated NaHCO₃aqueous solution. The mixture was extracted with DCM, washed withsaturated NaHCO₃ aqueous solution and brine, dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel eluting with ethyl acetate and petroleumether (4:1) to yield the desired product (631 mg, 57% yield, 2 steps) asa yellow solid. ESI-MS m/z: 429.3 [M+H]⁺.

tert-Butyl 4-(7-chloro-6-phenylquinazolin-4-yl)piperazine-1-carboxylate

A mixture of tert-butyl4-(6-bromo-7-chloroquinazolin-4-yl)piperazine-1-carboxylate (200 mg,0.47 mmol), phenylboronic acid (115 mg, 0.94 mmol), Na₂CO₃ solution (2.0M, 0.71 mL, 1.41 mmol), Pd(PPh₃)₄ (109 g, 0.094 mmol) in 1,4-dioxane (10mL) was stirred at reflux under argon for 16 h. The mixture was allowedto cool to RT, diluted with ethyl acetate, and then washed with H₂O andbrine. The organic layer was dried over Na₂SO₄ and concentrated invacuo. The residue was purified by flash column chromatography on silicagel eluting with ethyl acetate and petroleum ether (1:4) to yield thedesired product (120 mg, 60% yield) as a yellow oil. ESI-MS m/z: 425.4[M+H]⁺.

1-(4-(7-Chloro-6-phenylquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

The title compound was prepared from tert-butyl4-(7-chloro-6-phenylquinazolin-4-yl)piperazine-1-carboxylate in twosteps following the procedure described in Example 1. ¹H NMR (400 MHz,CDCl₃) δ: 8.74 (s, 1H), 8.15 (s, 1H), 7.83 (s, 1H), 7.50-7.45 (m, 5H),6.58 (dd, J=16.8, 10.4 Hz, 1H), 6.36 (dd, J=16.4, 1.6 Hz, 1H), 5.77 (dd,J=10.4, 2.0 Hz, 1H), 3.92-3.81 (m, 8H). ESI-MS m/z: 379.3 [M+H]⁺.

Example 3 Synthesis of1-(4-(6-chloro-5-(2-chlorophenyl)-1H-indazol-3-ylamino)piperidin-1-yl)prop-2-en-1-one(31)

Compound 31 was prepared according to Method C as described below:

4-Methyl-N′-(2′,4,6-trichlorobiphenylcarbonyl)benzenesulfonohydrazide

To a stirred solution of 2′,4,6-trichlorobiphenyl-3-carbonyl chloride(5.5 g) in toluene at RT, NH₂NHTs (3.8 g, 20.3 mmol) was added and theresulting mixture was stirred at 75° C. overnight. The mixture wasallowed to cool to RT. The solid was collected by filtration and driedin vacuo to afford the desired product (6 g, 75% yield) as a whitesolid.

2′,4,6-Trichloro-′-tosylbiphenyl-3-carbohydrazonoyl chloride

A solution of4-methyl-′-(2′,4,6-trichlorobiphenylcarbonyl)benzenesulfonohydrazide(2.3 g, 4.5 mmol) in SOCl₂ (5.8 g, 45 mmol) was stirred at 75° C. for 4h. The mixture was allowed to cool to RT, and then petroleum ether wasadded. The resulting mixture was stirred at 0° C. for 1 h. Theprecipitate was collected by filtration and dried in vacuo to afford thedesired product (1.6 g, 67% yield) as a white solid.

tert-Butyl4-((6-chloro-5-(2-chlorophenyl)-1-tosyl-1H-indazol-3-yl)(4-methoxybenzyl)amino)piperidine-1-carboxylate

To a stirred solution of2′,4,6-trichloro-′-tosylbiphenyl-3-carbohydrazonoyl chloride (1.6 g, 3.4mmol) in 100 mL of NMP at RT, tert-butyl4-(4-methoxybenzylamino)piperidine-1-carboxylate (1.1 g, 3.4 mmol) wasadded followed by K₂CO₃ (1.4 g, 10.2 mmol). The reaction mixture wasstirred at 40° C. overnight. The mixture was allowed to cool to RT, andpartitioned between water and ethyl acetate. The organic layer was driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residuewas purified by flash column chromatography on silica gel (1-20% ethylacetate/petroleum ether) to afford the desired product (550 mg, 23%yield) as a white solid.

tert-Butyl4-((6-chloro-5-(2-chlorophenyl)-1H-indazol-3-yl)(4-methoxybenzyl)amino)piperidine-1-carboxylate

To a stirred solution of tert-butyl4-((6-chloro-5-(2-chlorophenyl)-1-tosyl-1H-indazol-3-yl)(4-methoxybenzyl)amino)piperidine-1-carboxylate (550 mg, 0.75 mmol) in THF (20 mL) and water (5mL) at RT, NaOH (75 mg, 1.87 mmol) was added, and the resulting mixturewas stirred at reflux overnight. The reaction mixture was cooled to RTand partitioned between water and ethyl acetate. The organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by flash column chromatography on silica gel (1-10%ethyl acetate/petroleum ether) to afford the desired product (100 mg,23% yield) as a white solid. ESI-MS m/z: 581.5 [M+H]⁺.

6-Chloro-5-(2-chlorophenyl)-N-(piperidin-4-yl)-1H-indazol-3-amine

A solution of tert-butyl4-((6-chloro-5-(2-chlorophenyl)-1H-indazol-3-yl)(4-methoxybenzyl)amino)piperidine-1-carboxylate (100 mg, 0.17 mmol) in 5 mL of TFA was stirredat reflux for 2 h. The reaction mixture was allowed to cool to RT andthen partitioned between saturated NaHCO₃ aqueous solution and ethylacetate. The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to afford the desired product (62 mg) as a yellowsolid. The crude product was used directly in the next step withoutfurther purification.

1-(4-(6-Chloro-5-(2-chlorophenyl)-1H-indazol-3-ylamino)piperidin-1-yl)prop-2-en-1-one

To a stirred solution of acrylic acid (12.4 mg, 0.17 mmol) in 5 mL ofDMF at RT,6-chloro-5-(2-chlorophenyl)-N-(piperidin-4-yl)-1H-indazol-3-amine (62mg, 0.17 mmol), HOBT (30 mg, 0.22 mmol), EDCI (42 mg, 0.22 mmol), andTEA (52 mg, 0.51 mmol) were added sequentially. The reaction mixture wasstirred at RT overnight. The mixture was partitioned between brine andethyl acetate. The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified byprep-HPLC to give the desired product (2 mg, 3% yield) as a white solid.¹H NMR (300 MHz, DMSO-d6) δ: 11.67 (s, 1H), 7.73 (s, 1H), 7.56-7.58 (m,1H), 7.41-7.47 (m, 2H), 7.42 (s, 1H), 7.36-7.39 (m, 1H), 6.80-6.87 (m,1H), 6.07 (dd, J=2.5, 16.7 Hz, 1H), 6.04 (d, J=7.3 Hz, 1H), 5.65 (dd,J=2.4, 10.4 Hz, 1H), 4.23 (d, J=12.3 Hz, 1H), 3.98 (d, J=13.6 Hz, 1H),3.76-3.80 (m, 1H), 3.26 (t, J=13.0 Hz, 1H), 2.97 (t, J=10.2 Hz, 1H),2.06 (m, 2H), 1.38 (m, 2H). ESI-MS m/z: 415.1 [M+H]⁺.

Example 4 Synthesis of1-(4-(6-chloro-7-(2-chlorophenyl)isoquinolin-1-yl)piperazin-1-yl)prop-2-en-1-one(24)

Compound 24 was prepared according to Method D as described below:

N-(3-Bromo-4-chlorobenzyl)-2,2-diethoxyethanamine

To a solution of 3-bromo-4-chlorobenzaldehyde (10.0 g, 45 mmol) and2,2-diethoxyethanamine (6.68 g, 50 mmol) in 200 mL of DCM at RT, 0.5 mLof AcOH was added and the resulting mixture was stirred at RT for 30min. To this mixture, NaCNBH₃ (8.1 g, 135 mmol) was added in portionsand then stirred at RT overnight. The reaction mixture was portionedbetween water and DCM. The organic layer was washed with water (80 mL×2)and brine, dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to afford the desired product (11 g, 72% yield) as an oil. Thecrude product obtained was used directly in the next step withoutfurther purification.

N-(3-Bromo-4-chlorobenzyl)-2,2-diethoxy-N-tosylethanamine

To a solution of N-(3-bromo-4-chlorobenzyl)-2,2-diethoxyethanamine (11g, 33 mmol) in 100 mL of DCM, pyridine (10 mL) was added and theresulting mixture was cooled to 0° C. To this mixture, a solution of4-methylbenzene-1-sulfonyl chloride (6.8 g, 36 mmol) in 50 mL of DCM wasadded dropwise. The reaction mixture was allowed to warm to RT andstirring was continued until conversion was completed. The reactionmixture was washed twice with HCl aqueous solution (2 M), sodiumbicarbonate solution and brine. The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (5-20% ethylacetate/petroleum ether) to afford the desired product (12.5 g, 78%yield). ESI-MS m/z: 490.2 [M+H]⁺.

7-Bromo-6-chloroisoquinoline

AlCl₃ (14.9 g) was suspended in DCM at RT, a solution ofN-(3-bromo-4-chlorobenzyl)-2,2-diethoxy-N-tosylethanamine (11.0 g, 22.5mmol) in 75 mL of DCM was added and the resulting mixture was stirredovernight. The mixture was poured into ice water, and extracted withDCM. The combined organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel (10-40% ethyl acetate/petroleumether) to afford the desired product (5 g, 92.5% yield) as a whitesolid. ESI-MS m/z: 242 [M+H]⁺.

7-Bromo-6-chloroisoquinoline2-oxide

To a solution of 7-bromo-6-chloroisoquinoline (5.5 g, 22.8 mmol) in 100mL of DCM at RT, was added m-chloroperbenzoic acid (70%, 5.88 g, 34.2mmol) and the resulting mixture was stirred at RT overnight. Theprecipitate was filtered off and rinsed with DCM. The filtrate waswashed with sodium bicarbonate solution. The layers were separated andthe aqueous layer was extracted with DCM. The combined organic layer wasdried with anhydrous Na₂SO₄ and concentrated in vacuo to afford thedesired product (4.6 g, 79% yield). The crude product was used directlyin the next step without further purification. ESI-MS m/z: 258.2 [M+H]⁺.

1-(4-(6-chloro-7-(2-chlorophenyl)isoquinolin-1-yl)piperazin-1-yl)prop-2-en-1-one

The title compound was prepared from 7-Bromo-6-chloroisoquinoline2-oxidein five steps following the procedure described in Example 1. ¹H NMR(400 MHz, DMSO-d6) δ: 8.22-8.21 (m, 2H), 8.00 (s, 1H), 7.65-7.47 (m,5H), 6.87 (dd, J=16.9, 10.5 Hz, 1H), 6.16 (dd, J=16.7, 1.7 Hz, 1H), 5.72(dd, J=10.3, 2.1 Hz, 1H), 3.83 (m, 4H), 3.37 (m, 4H). ESI-MS m/z: 412.2[M+H]⁺.

Example 5 Synthesis of1-(4-(7-chloro-6-(2-chlorophenyl)quinolin-4-yl)piperazin-1-yl)prop-2-en-1-one(27)

Compound 27 was prepared according to Method E as described below:

Diethyl 2-((3-chloro-4-iodophenylamino)methylene)malonate

3-Chloro-4-iodoaniline (3.0 g, 11.8 mmol) and diethyl2-(ethoxymethylene)malonate (12.78 g, 59.2 mmol) were mixed in a 100 mLsingle neck flask, and the resulting mixture was heated to 120° C. andstirred for 2.5 h. The mixture was allowed to cool to RT and purified byflash column chromatography on silica gel (10-20% ethylacetate/petroleum ether) to afford the desired product (3.93 g) as awhite solid. ESI-MS m/z: 422.1 [M−H]⁻.

Ethyl 7-chloro-4-hydroxy-6-iodoquinoline-3-carboxylate

(E)-diethyl 2-(((3-chloro-4-iodophenyl)imino)methyl) malonate (2.0 g,4.73 mmol) was suspended in 30 mL of Ph₂O. The mixture was stirred at250° C. for 4 h. The mixture was allowed to cool to RT and then 100 mLof petroleum ether was added. The white solid was collected byfiltration and rinsed with petroleum ether (100 mL) to afford thedesired product (1.20 g) as a white solid.

7-Chloro-4-hydroxy-6-iodoquinoline-3-carboxylic acid

Ethyl 7-chloro-4-hydroxy-6-iodoquinoline-3-carboxylate (1.2 g, 3.18mmol) was suspended in 10% NaOH aqueous solution (50 mL). The mixturewas stirred at reflux for 3.5 h. The white solid was slowly dissolved inNaOH solution. After the mixture turned to a colorless phase, it waskept heating for additional 1 h. The mixture was allowed to cool to RT,and the white solid was separated out. The mixture was acidified withcon. HCl to adjust the pH to 2. The white precipitate was collected byfiltration and rinsed with petroleum ether to afford the desired product(1.13 g) as a white solid.

7-Chloro-6-iodoquinolin-4-ol

7-Chloro-4-hydroxy-6-iodoquinoline-3-carboxylic acid (1.134 g, 3.25mmol) was suspended in 40 mL of Ph₂O. The mixture was stirred at 250° C.for 3.5 h. The mixture was allowed to cool to RT and 100 mL of petroleumether was added. The solid was collected by filtration, and rinsed withpetroleum ether to afford the desired product (0.92 g) as a white solid.

4,7-Dichloro-6-iodoquinoline

7-Chloro-6-iodoquinolin-4-ol (591 mg, 1.94 mmol) was dissolved in 40 mLof POCl₃ and the mixture was stirred at reflux for 3 h. The mixture wasallowed to cool to RT and concentrated in vacuo. The residue was pouredinto a solution of Et₃N (2.93 g, 29.03 mmol, 15 eq.) in 40 mL of DCM at0° C. The mixture was partitioned between ethyl acetate and brine. Theorganic layer was dried and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (40% ethylacetate/petroleum ether) to afford the desired product (895 mg) as asolid. ESI-MS m/z: 323.9 [M+H]⁺.

tert-Butyl 4-(7-chloro-6-iodoquinolin-4-yl)piperazine-1-carboxylate

4,7-Dichloro-6-iodoquinoline (200 mg, 0.62 mmol) was mixed withtert-butyl piperazine-1-carboxylate (172 mg, 0.93 mmol) and Et₃N (250mg, 2.47 mmol) in 15 mL DMSO. The resulting mixture was stirred at 80°C. under argon for 16 h. The mixture was poured into 250 mL of water and50 mL of brine, and then extracted with ethyl acetate. The combinedorganic layer was washed with brine, dried over Na₂SO₄, and concentratedin vacuo. The residue was purified by flash column chromatography onsilica gel (20-30% ethyl acetate/petroleum ether) to afford the desiredproduct (132 mg). ESI-MS m/z: 374.2 [M+H]⁺.

tert-Butyl4-(7-chloro-6-(2-chlorophenyl)quinolin-4-yl)piperazine-1-carboxylate

tert-Butyl 4-(7-chloro-6-iodoquinolin-4-yl)piperazine-1-carboxylate (130mg, 0.28 mmol) was mixed with (2-chlorophenyl)boronic acid (109 mg, 0.33mmol), Pd(PPh₃)₄ (32 mg, 0.028 mmol) and Na₂CO₃ (88 mg, 0.83 mmol) in1,4-dioxane (20 mL) and water (4 mL). The mixture was stirred at 70° C.under argon for 4 h. The mixture was allowed to cool to RT andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (30-40% ethyl acetate/petroleum ether) toafford the desired (100 mg). ESI-MS m/z: 458.3 [M+H]⁺.

1-(4-(7-Chloro-6-(2-chlorophenyl)quinolin-4-yl)piperazin-1-yl)prop-2-en-1-one

tert-butyl4-(7-chloro-6-(2-chlorophenyl)quinolin-4-yl)piperazine-1-carboxylate(100 mg, 0.22 mmol) was dissolved in 20% MeOH-HCl solution (20 mL). Themixture was stirred at RT for 1 h. The mixture was concentrated in vacuoto yield a yellow solid salt (124 mg). The yellow salt (124 mg, 0.32mmol) was dissolved in 30 mL of DCM in the presence of Et₃N (191 mg,1.89 mmol). The mixture was cooled to 0° C. and then a solution ofacryloyl chloride (32 mg, 0.35 mmol) in DCM (2 mL) was added dropwise.The mixture was stirred at 0° C. for 30 min. The mixture wasconcentrated in vacuo and the residue was purified by flash columnchromatography on silica gel (50-100% ethyl acetate/petroleum ether) toafford the desired product (35 mg). ¹H NMR (300 MHz, DMSO-d6) δ:8.78-8-79 (m, 1H), 8.17 (s, 1H), 7.96 (s, 1H), 7.65-7.51 (m, 4H),7.10-7.09 (m, 1H), 6.87 (dd, J=16.4, 10.4 Hz, 1H), 6.15 (d, J=16.4 Hz,1H), 5.71 (d, J=10.4 Hz, 1H), 3.81 (br s, 4H), 3.22 (br s, 4H). ESI-MSm/z: 412.2 [M+H]⁺.

Example 6 Synthesis of4-(4-acryloylpiperazin-1-yl)-7-chloro-6-(4-chlorophenyl)quinoline-3-carbonitrile(42)

Compound 42 was prepared according to Method G as described below:

3-Chloro-4-(4-chlorophenyl)benzenamine

A mixture of 3-chloro-4-iodobenzenamine (500 mg, 1.97 mmol),4-chlorophenylboronic acid (324 mg, 2.07 mmol), Na₂CO₃ (627 mg, 5.92mmol) and Pd(PPh₃)₄ (228 mg, 0.20 mmol) in 1,4-dioxane (21 mL) and H₂O(4 mL) was stirred at 80° C. under argon for 16 h. The mixture wasallowed to cool to RT and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (ethylacetate/petroleum ether=5/1) to afford the desired product (424 mg, 91%yield) as a yellow solid.

(E)-Ethyl 3-(3-chloro-4-(4-chlorophenyl)-phenylamino)-2-cyanoacrylate

A mixture of 3-chloro-4-(4-chlorophenyl)benzenamine (250 mg, 1.05 mmol)and (E)-ethyl 2-cyano-3-ethoxyacrylate (186 mg, 1.10 mmol) was stirredat 100° C. for 2 h and then at 130° C. for 4 h. The mixture was allowedto cool to RT and concentrated in vacuo. The residue was triturated withethyl acetate to afford the desired product (219 mg, 55% yield) as awhite solid. ESI-MS m/z: 359.1 [M−H]⁻.

7-chloro-6-(4-chlorophenyl)-4-hydroxyquinoline-3-carbonitrile

A mixture of(E)-Ethyl-3-(3-chloro-4-(4-chlorophenyl)-phenylamino)-2-cyanoacrylate(219 mg, 0.608 mmol) in Ph₂O (8 mL) was stirred at 253° C. for 4 h. Themixture was cooled to RT and poured into petroleum ether (20 mL). Theprecipitate was collected by filtration and washed with petroleum ether(50 mL×2) to yield the desired product (65 mg, 34% yield) as a brownsolid.

4-(4-acryloylpiperazin-1-yl)-7-chloro-6-(4-chlorophenyl)quinoline-3-carbonitrile

The title compound was prepared from7-chloro-6-(4-chlorophenyl)quinolin-4-ol in four steps according to theprocedure described in Example 1. ¹H NMR (400 MHz, DMSO-d6) δ: 8.84 (s,1H), 8.21 (s, 1H), 8.05 (s, 1H), 7.66-7.59 (m, 4H), 6.88 (dd, J=16.8,10.4 Hz, 1H), 6.17 (dd, J=16.8, 2.0 Hz, 1H), 5.74 (dd, J=10.4, 2.0 Hz,1H), 3.83-3.74 (m, 8H). ESI-MS m/z: 437.2 [M+H]⁺.

Example 7 Synthesis of1-(4-(5-(4-chlorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one(22)

Compound 22 was prepared according to Method H as described below:

tert-Butyl4-(5-(4-chlorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

A solution of 4-chloro-5-(4-chlorophenyl)thieno[2,3-d]pyrimidine (180mg, 0.64 mmol), tert-butyl piperazine-1-carboxylate (119 mg, 0.64 mmol)and diisopropyl amine in THF (6 mL) was stirred at RT overnight. Themixture was partitioned between DCM and water. The organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuo to afford thedesired product which was used directly in the next step without furtherpurification.

5-(4-Chlorophenyl)-4-(piperazin-1-yl)thieno[2,3-d]pyrimidinehydrochloride

To a suspension of tert-butyl4-(5-(4-chlorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylateobtained from the previous step in 1,4-dioxane (10 mL) and MeOH (5 mL),was added a solution of HCl in 1,4-dioxane (4 M, 1.0 mL). The mixturewas stirred at RT overnight. The mixture was concentrated in vacuo andthe residue was used directly in the next step without furtherpurification.

1-(4-(5-(4-Chlorophenyl)thieno[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

To a solution of5-(4-Chlorophenyl)-4-(piperazin-1-yl)thieno[2,3-d]pyrimidinehydrochloride obtained above in DCM (10 mL) at 0° C., Et₃N (0.2 mL) wasadded followed by acryloyl chloride. The resulting mixture was allowedto warm to RT and stirred for 1 h. The mixture was partitioned betweenDCM and water. The organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified via Isolera One (silicacartridge, 0-60% ethyl acetate/hexanes) to afford the desired product(27.5 mg). ¹H NMR (300 MHz, CDCl₃), δ: 8.64 (s, 1H), 7.35-7.48 (m, 4H),7.30 (s, 1H), 6.42-6.60 (m, 1H), 6.26 (d, J=24 Hz, 1H), 5.69 (d, J=10.5Hz, 1H), 3.10-3.35 (m, 8H). ESI-MS m/z: 385.0 [M+H]⁺

Example 8 Synthesis of1-(4-(8-(2-chlorophenyl)quinazolin-2-yl)piperazin-1-yl)prop-2-en-1-one(35)

Compound 35 was prepared according to Method I as described below:

tert-Butyl 4-(8-bromoquinazolin-2-yl)piperazine-1-carboxylate

The title compound was prepared from 8-bromo-2-chloroquinazolineaccording to the procedure described in step 1 in Example 7.

tert-Butyl 4-(8-(2-chlorophenyl)quinazolin-2-yl)piperazine-1-carboxylate

A mixture of tert-Butyl4-(8-bromoquinazolin-2-yl)piperazine-1-carboxylate (250 mg, 0.64 mmol),2-chlorophenylbronic acid (110 mg, 1.1 mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (50mg) in a mixture of 1,4-dioxane (6 mL) and sat. NaHCO₃ solution (3 mL)was stirred at 100° C. for 1 h. The mixture was allowed to cool to RT,and partitioned between water and ethyl acetate. The organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified via Isolera One (silica cartridge, 0-60% ethyl acetate/hexanes)to afford the desired product.

1-(4-(8-(2-Chlorophenyl)quinazolin-2-yl)piperazin-1-yl)prop-2-en-1-one

The title compound was prepared from tert-Butyl4-(8-(2-chlorophenyl)quinazolin-2-yl)piperazine-1-carboxylate accordingto the procedure described in steps 2 and 3 in Example 7. ¹H NMR (300MHz, CDCl₃) δ: 9.07 (s, 1H), 7.74 (dd, J=8.0, 1.6 Hz, 1H), 7.67 (dd,J=6.8, 1.2 Hz, 1H), 7.46-7.56 (m, 1H), 7.39-7.42 (m, 4H), 6.58 (dd,J=16.8, 10.8 Hz, 1H), 6.32 (dd, J=16.8, 2.0 Hz, 1H), 5.71 (dd, J=10.6,1.9 Hz, 1H), 3.8-3.9 (br., 4H), 3.68-3.78 (br., 2H), 3.55-3.62 (br.,2H). ESI-MS m/z: 379.1 [M+H]⁺.

Example 9 Synthesis of1-(4-(5-(2-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one(28)

Compound 28 was prepared according to Method J as described below:

4-Chloro-7H-pyrrolo[2,3]pyrimidine

A mixture of 1H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (2.5 g. 18.6 mmol) in46 mL of POCl₃ was stirred at reflux for 5 h. The mixture was allowed tocool to RT and then concentrated in vacuo to remove the excess amount ofPOCl₃. Ice was added to the residue and the mixture was stirred at RTfor 10 min. The aqueous layer was extracted with diethyl ether. Theorganic layer was dried over MgSO₄, filtered, and concentrated in vacuoto afford the desired product (1.5 g, 54% yield) as an off-white solid.

4-Chloro-5-iodo-7H-pyrrolo[2,3]pyrimidine

4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (1.8 g 11.9 mmol) andN-iodosuccinamide (3 g, 13.1 mmol) were mixed in a round bottomed flask.The flask was dried under high vacuum for 5 h and then back-filled withargon. To this mixture, dry DMF (100 mL) was added and the resultingmixture was stirred in the dark for 20 h. The reaction was quenched withmethanol and concentrated in vacuo. The residue was diluted with 150 mLof DCM and washed with water (200 mL), saturated aqueous sodium sulfite(200 mL), and brine (100 mL). The organic layer was dried over MgSO₄,filtered, and concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel (50% ethyl acetate/hexanes) toafford the desired product (3.1 g, 95% yield) as a white solid. ESI-MSm/z: 279.5 [M+H]⁺.

4-Chloro-5-iodo-7benzenesulfonyl-pyrrolo[2,3-d]pyrimidine

To a solution of 4-chloro-5-iodo-7H-pyrrolo[2,3]pyrimidine (280 mg, 1mmol) in DMF (5 mL) at 0° C., NaH (60%, 52 mg, 1.3 mmol) was added andthe resulting mixture was stirred at 0° C. for 30 min. To this mixture,benzenesulfonyl chloride (194 mg, 1.1 mmol) was added. The mixture wasthen stirred at RT for 2 h. The mixture was partitioned between ethylacetate and water. The organic layer was dried over MgSO₄, filtered, andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel to afford the desired product (300 mg,71.6% yield).

4-Chloro-5-(2-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidine

To a solution of4-chloro-5-iodo-7benzenesulfonyl-pyrrolo[2,3-d]pyrimidine (300 mg, 0.71mmol) and 2-chlorophenylboronic acid (167 mg, 1.07 mmol) in 1,4-dioxane(15 mL) and water (3 mL), Pd(PPh₃)₄ (60 mg) and Na₂CO₃ (227 mg, 2.14mmol) were added. The mixture was stirred at 80° C. overnight. Themixture was allowed to cool to RT and concentrated in vacuo. The residuewas purified by flash column chromatography on silica gel to afford thedesired product (120 mg, 63% yield). ESI-MS m/z: 262.2 [M−H]⁻.

tert-butyl-4-(5-(2-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate

To a solution of 4-chloro-5-(2-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidine(120 mg, 0.45 mmol) and tert-butyl piperazine-1-carboxylate (254 mg,1.36 mmol) in 1,4-dioxane (15 mL), DIEA (293 mg, 2.27 mmol) was added.The mixture was stirred at 100° C. overnight. The mixture wasconcentrated in vacuo and the residue was purified by flash columnchromatography on silica gel to afford the desired product (120 mg, 64%yield).

1-(4-(5-(2-Chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

The title compound was prepared fromtert-butyl-4-(5-(2-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylatein two steps according to the procedure described in Example 1. ¹H NMR(400 MHz, DMSO-d6) δ: 8.5 (s, 1H), 7.5 (m, 1H), 7.4 (m, 3H), 7.3 (s,2H), 6.5 (m, 1H), 6.3 (m, 1H), 5.7 (m, 1H), 3.4 (m, 8H). ESI-MS m/z:368.3 [M+H]⁺.

Example 10 Synthesis of1-(4-(2-amino-7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one(39) and1-(4-(7-chloro-6-(4-chlorophenyl)-2-methoxyquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one(43)

Compounds 39 and 43 were prepared according to Method F as describedbelow:

6-Bromo-7-chloroquinazoline-2,4-diol

A mixture of methyl 2-amino-5-bromo-4-chlorobenzoate (3.0 g, 11.34 mmol)and urea (1.36 g, 22.68 mmol, 2 eq.) was stirred at 200° C. for 3 h. Themixture was allowed to cool to RT, triturated with ethyl acetate anddried to afford the desired product (2.39 g) as a brown solid.

6-Bromo-2,4,7-trichloroquinazoline

The mixture of 6-bromo-7-chloroquinazoline-2,4-diol (1.1 g, 6.79 mmol)in 30 mL of POCl₃ was stirred at reflux for 2 days. The mixture wasallowed to cool to RT and concentrated in vacuo to remove POCl₃. Theresidue was poured into a solution of Et₃N (13.7 g, 20 eq.) in 30 mL ofDCM at 0° C. The mixture was partitioned between ethyl acetate andbrine. The organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash chromatographyon silica gel (5-10% ethyl acetate/petroleum ether) to afford thedesired product (474 mg) as a yellow solid.

tert-Butyl-4-(6-bromo-2,7-dichloroquinazolin-4-yl)piperazine-1-carboxylate

To a solution of tert-butyl piperazine-1-carboxylate (123 mg, 0.66 mmol)in DMF (10 mL) at RT, DIEA (94 mg, 0.72 mmol) was added followed by6-bromo-2,4,7-trichloroquinazoline (206 mg, 0.66 mmol). The resultingmixture was stirred at 50° C. for 40 min. The mixture was allowed tocool to RT and partitioned between water and ethyl acetate. The organiclayer was washed with brine, dried over Na₂SO₄ and concentrated. Theresidue was purified by flash column chromatography on silica gel (5%ethyl acetate/petroleum ether) to afford the desired product (222 mg) asa yellow solid. ESI-MS m/z: 463.2 [M+H]⁺.

tert-Butyl4-(6-bromo-7-chloro-2-methoxyquinazolin-4-yl)piperazine-1-carboxylate

To a solution of NaOMe (26 mg, 0.476 mmol) in MeOH (20 mL),tert-butyl-4-(6-bromo-2,7-dichloroquinazolin-4-yl)piperazine-1-carboxylate(110 mg, 0.238 mmol) was added. The mixture was stirred at 60° C. underargon for 40 min. The mixture was quenched by water (1.0 mL) and thenconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (10-20% ethyl acetate/petroleum ether) toafford the desired product (55 mg) as a yellow solid. ESI-MS m/z: 459.2[M+H]⁺.

tert-Butyl-4-(7-chloro-6-(4-chlorophenyl)-2-methoxyquinazolin-4-yl)piperazine-1-carboxylate

The mixture of tert-butyl4-(6-bromo-7-chloro-2-methoxyquinazolin-4-yl)piperazine-1-carboxylate(85 mg, 0.19 mmol), (4-chlorophenyl)boronic acid (35 mg, 0.22 mmol),Pd(PPh₃)₄ (22 mg, 0.019 mmol), Na₂CO₃ (60 mg, 0.56 mmol) in dioxane (20mL) and water (2 mL) was stirred at 80° C. under argon for 16 h. Themixture was allowed to cool to RT and concentrated in vacuo. The residuewas purified by flash column chromatography on silica gel (10-20% ethylacetate/petroleum ether) followed by Prep-TLC to afford the desiredproduct (100 mg) as a white solid. ESI-MS m/z: 489.4 [M+H]⁺.

1-(4-(7-Chloro-6-(4-chlorophenyl)-2-methoxyquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

tert-Butyl-4-(7-chloro-6-(4-chlorophenyl)-2-methoxyquinazolin-4-yl)piperazine-1-carboxylate(100 mg, 0.20 mmol) was dissolved in 20 mL of 20% HCl methanol solution.The mixture was stirred at RT for 1 h and then concentrated in vacuo toyield a yellow solid salt (90 mg).

The above yellow solid (90 mg, 0.21 mmol) was dissolved in 30 mL of DCMwith Et₃N (129 mg, 1.27 mmol). The mixture was cooled to 0° C. and thenadded dropwise to a solution of acryloyl chloride (23 mg, 0.25 mmol) inDCM (2 mL). The resulting mixture was stirred at 0° C. for 30 min. Themixture was poured into H₂O (100 mL), sat. NaHCO₃ (50 mL) and brine (50mL), and then extracted with ethyl acetate. The organic layer was washedwith brine, dried over Na₂SO₄ and concentrated. The residue was purifiedby Prep-TLC followed by Prep-HPLC to afford the desired product (8 mg)as a white solid. ESI-MS m/z: 443.2 [M+H]⁺.

tert-Butyl-4-(2-amino-6-bromo-7-chloroquinazolin-4-yl)piperazine-1-carboxylate

The mixture of tert-butyl4-(6-bromo-2,7-dichloroquinazolin-4-yl)piperazine-1-carboxylate in sat.NH₃-EtOH (4 mL) in a sealed tube was stirred at 100° C. for 16 h. Themixture was allowed to cool to RT and concentrated in vacuo. The residuewas purified by flash column chromatography on silica gel (20-30% ethylacetate/petroleum ether) to afford the desired product (70 mg) as awhite solid.

tert-Butyl-4-(2-amino-7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazine-1-carboxylate

The mixture oftert-butyl-4-(2-amino-6-bromo-7-chloroquinazolin-4-yl)piperazine-1-carboxylate(70 mg, 0.16 mmol), (4-chlorophenyl)boronic acid (29 mg, 0.19 mmol),Pd(PPh₃)₄ (18 mg, 0.019 mmol), and Na₂CO₃ (50 mg, 0.48 mmol) in dioxane(20 mL) and water (2 mL) was stirred at 80° C. under argon for 16 h. Themixture was allowed to cool to RT and then concentrated in vacuo. Theresidue was purified by flash column chromatography on silica gel(10-20% ethyl acetate/petroleum ether) followed by Prep-TLC to affordthe desired product (70 mg) as a red solid. ESI-MS m/z: 474.5[M+H]⁺.

1-(4-(2-Amino-7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

tert-Butyl-4-(2-amino-7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazine-1-carboxylate(70 mg, 0.15 mmol) was dissolved in 20% HCl methanol solution (20 mL)and the resulting mixture was stirred at RT for 1 h. The mixture wasconcentrated to afford the desired product (70 mg) as a yellow solidsalt.

The mixture of above obtained yellow solid (70 mg, 0.21 mmol), acrylicacid (18 mg, 0.25 mmol), EDCI (73 mg, 0.381 mmol) and HOBT (52 mg, 0.381mmol) in 10 mL of DMF at 0° C., a solution of Et₃N (120 mg, 1.2 mmol) inDCM (2 mL) was added dropwise. The resulting mixture was stirred at 0°C. for 30 min and at RT for 1.5 h. The mixture was poured into water(100 mL), sat. NaHCO₃ (50 mL) and brine (50 mL), and then extracted withethyl acetate. The organic layer was washed with brine, dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel to yield the desired product (5 mg)as a gray solid. ESI-MS m/z: 428.3 [M+H]⁺.

Example 11 Synthesis of1-(4-(7-chloro-6-(2-chlorophenyl)quinazolin-4-yl)piperidin-1-yl)prop-2-en-1-one(36)

Compound 36 was prepared according to Method K as described below:

1-tert-Butyl 4-methyl4-(6-bromo-7-chloroquinazolin-4-yl)piperidine-1,4-dicarboxylate

To a stirred solution of tert-butyl methyl piperidine-1,4-dicarboxylate(3.3 g, 13.5 mmol) in anhydrous THF (30 mL) at 0° C. under nitrogen,LiHMDS (15 mL, 15 mmol) was added and the resulting mixture was stirredat 0° C. for 1 h. To this mixture, a solution of6-bromo-4,7-dichloroquinazoline (748 mg, 2.7 mmol) in THF (5 mL) wasadded and the resulting mixture was stirred at room temperature for 4 h.The mixture was quenched with ice-water and partitioned between waterand ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel (1-10% ethyl acetate/petroleumether) to afford the desired product (580 mg, 37% yield) as a whitesolid.

tert-Butyl 4-(6-bromo-7-chloroquinazolin-4-yl)piperidine-1-carboxylate

To a solution of 1-tert-butyl 4-methyl4-(6-bromo-7-chloroquinazolin-4-yl)piperidine-1,4-dicarboxylate (483 mg,1.2 mmol) in DMSO (10 mL), LiCl (103 mg, 2.4 mmol) and water (65 mg, 3.6mmol) were added, and the rusting mixture was stirred at 110° C. for 16h. The mixture was allowed to cool to room temperature and partitionedbetween water and ethyl acetate. The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (1-20% ethylacetate/petroleum ether) to afford the desired product (170 mg, 33%yield) as a white solid.

tert-Butyl4-(7-chloro-6-(2-chlorophenyl)quinazolin-4-yl)piperidine-1-carboxylate

A mixture of tert-butyl4-(6-bromo-7-chloroquinazolin-4-yl)piperidine-1-carboxylate (230 mg,0.59 mmol), 2-chlorophenylboronic acid (138 mg, 0.88 mmol), Pd(PPh₃)₄(69 mg, 0.06 mmol) and Na₂CO₃ (188 mg, 106 mmol) in 1,4-dioxane (10 mL)under argon was stirred at 100° C. for 16 h. The mixture was allowed tocool to room temperature, and partitioned between water and ethylacetate. The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (1-20% ethyl acetate/petroleum ether) toafford the desired product (160 mg, 65% yield) as a white solid.

1-(4-(7-Chloro-6-(2-chlorophenyl)quinazolin-4-yl)piperidin-1-yl)prop-2-en-1-one(45)

The title compound was prepared from tert-butyl4-(7-chloro-6-(2-chlorophenyl) quinazolin-4-yl)piperidine-1-carboxylateaccording to the procedure described in steps 5 and 6 in Example 1. ¹HNMR (400 MHz, DMSO-d6) δ: 9.28 (s, 1H), 8.55 (s, 1H), 8.27 (s, 1H), 7.70(m, 2H), 7.53-7.68 (m, 2H), 6.82-6.88 (m, 1H), 6.10 (dd, J=2.5, 16.8 Hz,1H), 5.68 (dd, J=2.3, 10.3 Hz, 1H), 4.55 (d, J⁼12.2 Hz, 1H), 4.09-4.16(m, 2H), 3.32 (t, J=12.2 Hz, 1H), 2.89 (t, J=12.1 Hz, 1H), 1.72-1.93 (m,4H). ESI-MS m/z: 410.35 [M−H]⁻.

Example 12 Synthesis of7-chloro-6-(4-chlorophenyl)-4-(4-(vinylsulfonyl)piperazin-1-yl)quinazoline(45)

Compound 45 was prepared according to the general procedures of Method Aas described below:

tert-Butyl4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazine-1-carboxylate

The title compound was prepared from tert-butyl4-(6-bromo-7-chloroquinazolin-4-yl)piperazine-1-carboxylate and4-chlorophenylboronic acid according to the procedure described in step4 in Example 2.

tert-Butyl4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazine-1-carboxylate

A solution oftert-butyl4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazine-1-carboxylate(500 mg, 1.09 mmol) in HCl/MeOH (10 mL, 28.6 mmol) was stirred at roomtemperature for 30 min. The mixture was concentrated in vacuo to affordthe crude product.

7-Chloro-6-(4-chlorophenyl)-4-(4-(vinylsulfonyl)piperazin-1-yl)quinazoline

The above obtained crude product was dissolved with DCM (15 mL) andcooled to 0° C. To this mixture, 2-chloroethanesulfonyl chloride (213.2mg, 1.31 mmol) and Et₃N (1.5 mL, 10.9 mmol) were added and the resultingmixture was stirred at 0° C. for 10 min. The mixture was quenched withice-water and partitioned between water and ethyl acetate. The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified by prep-HPLC to afford the desiredproduct (3 mg, 0.6% yield). ¹H-NMR (400 M Hz, CDCl₃) δ: 8.78 (s, 1H),8.08 (s, 1H), 7.75 (s, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz,2H), 6.46 (dd, J=10, 16.8 Hz, 1H), 6.31 (d, J⁼16.8 Hz, 1H), 6.11 (d,J=9.6 Hz, 1H), 3.91 (t, J=4.8 Hz, 4H), 3.35 (t, J=4.8 Hz, 4H). ESI-MSm/z: 449.25 [M+H]⁺.

Example 13 Synthesis of1-(4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)-2-(hydroxymethyl)piperazin-1-yl)prop-2-en-1-one(46)

Compound 46 was prepared according to the general procedures of Method Aas described below:

4,7-Dichloro-6-(4-chlorophenyl)quinazoline

The title compound was prepared from 2-amino-5-bromo-4-chlorobenzoateaccording to the procedure described in steps 1, 2 and 3 in Example 1.

tert-Butyl4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylate

The above obtained crude 4,7-dichloro-6-(4-chlorophenyl)quinazoline (200mg, 0.464 mmol) was added to the mixture of tert-butyl2-(hydroxymethyl)piperazine-1-carboxylate (210 mg, 0.968 mmol) and DIEA(418 mg, 3.24 mmol) in 1,4-dioxane (20 mL) at room temperature and theresulting mixture was stirred at 80° C. for 3 h. The mixture was allowedto cool to room temperature and then concentrated in vacuo. The residuewas purified by flash column chromatography on silica gel(DCM/MeOH=30:1) to afford the desired product (110 mg, 35% yield) as alight yellow oil. ESI-MS m/z: 498.9 [M+H]⁺.

(4-(7-Chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazin-2-yl)methanolhydrochloride

A mixture of4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylate(110 mg, 0.225 mmol) and HCl in MeOH (10 mL, 28.6 mmol) was stirred atroom temperature for 1 h. The mixture was concentrated in vacuo toafford the crude product (106 mg) as a yellow solid which was useddirectly in next step without further purification.

1-(4-(7-Chloro-6-(4-chlorophenyl)quinazolin-4-yl)-2-(hydroxymethyl)piperazin-1-yl)prop-2-en-1-one

To a stirred solution of above obtained yellow solid (106 mg, 0.225mmol) in DMF (5 mL) at room temperature, acrylic acid (19 mg, 0.27mmol), BOP (149 mg, 0.338 mmol) and DIEA (203 mg, 1.58 mmol) were addedand the resulting mixture was stirred at room temperature for 30 min.The mixture was poured into saturated aqueous NaHCO₃ solution (50 mL),and then extracted with ethyl acetate. The organic layer was washed withbrine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (DCM/MeOH=20:1) toafford the desired product (20 mg, 20% yield, 2 steps) as a solid. ¹HNMR (400 MHz, DMSO-d6) δ: 8.7 (s, 1H), 8.2 (d, J=2.8 Hz, 1H), 8.0 (s,1H), 7.5 (m, 4H), 6.8 (dd, J=10.4, 16.4 Hz, 1H), 6.1 (d, J=17 Hz, 1H),5.7 (dd, J=2.4, 10.4 Hz, 1H), 5.0 (m, 1H), 4.3 (m, 2H), 4.2 (m, 2H), 3.6(m, 3H), 2.5 (s, 2H). ESI-MS m/z: 443.30 [M+H]⁺.

Example 14 Synthesis of1-acryloyl-4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazine-2-carbonitrile(47)

Compound 47 was prepared according to the general procedures of Method Aas described below:

4-(7-Chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazine-2-carboxamide

The crude 4,7-dichloro-6-(4-chlorophenyl)quinazoline (310 mg, 1 mmol)was added to the mixture of piperazine-2-carboxamide (249 mg, 1.5 mmol)and DIEA (645 mg, 5 mmol) in 1,4-dioxane (20 mL) at room temperature andthe resulting mixture was stirred at 80° C. for 2 h. The mixture wasallowed to cool to room temperature and then concentrated in vacuo. Theresidue was used in the next step without further purification.

ESI-MS m/z: 402.3 [M+H]⁺.

tert-Butyl2-carbamoyl-4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazine-1-carboxylate

To a solution of the above obtained crude product4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazine-2-carboxamidein DCM (20 mL) at room temperature, Et₃N (152 mg, 1.5 mmol) anddi-tert-butyl dicarbonate (262 mg, 1.2 mmol) were added. The mixture wasstirred at room temperature for 3 h. The mixture was concentrated invacuo and the residue was purified by flash column chromatography onsilica gel (DCM/MeOH=30:1) to afford the desired product (60 mg, 12%yield) as a solid. ESI-MS m/z: 502.4 [M+H]⁺.

tert-Butyl4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)-2-cyanopiperazine-1-carboxylate

To a solution of tert-butyl2-carbamoyl-4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazine-1-carboxylate(60 mg, 0.12 mmol) and Et₃N (48 mg, 0.48 mmol) in DCM (20 mL) at 0° C.,TFAA (50 mg, 0.24 mmol) and the resulting mixture was stirred at roomtemperature for 1 h. The reaction mixture was quenched with saturatedNaHCO₃ solution, and then extracted with DCM. The organic layer waswashed with saturated NaHCO₃ solution and brine, dried over Na₂SO₄ andconcentrated in vacuo.

The residue was purified by flash column chromatography on silica gel(DCM/MeOH=50:1) to afford the desired product (50 mg, 86% yield) as asolid. ESI-MS m/z: 484.4 [M+H]⁺.

1-Acryloyl-4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazine-2-carbonitrile

The title compound was prepared from tert-butyl4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)-2-cyanopiperazine-1-carboxylateaccording to the procedure described in steps 5 and 6 in Example 1. ¹HNMR (400 MHz, DMSO-d6) δ: 8.7 (s, 1H), 8.1 (s, 1H), 8.0 (d, J=2.0 Hz,1H), 7.5 (m, 4H), 6.8 (dd, J=10.4, 16.8 Hz, 1H), 6.3 (dd, J=1.6, 16.8Hz, 1H), 5.8 (dd, J=1.6, 10.4 Hz, 1H), 4.6 (m, 1H), 4.3 (m, 3H), 3.6 (m,2H), 3.4 (s, 1H). ESI-MS m/z: 438.25 [M+H]⁺.

Example 15 Synthesis of1-(4-(7-chloro-6-(4-chlorophenyl)-2-methylquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one(50)

Compound 50 was prepared according to the general procedures of Method Mas described below:

6-Bromo-7-chloro-2-methylquinazolin-4-ol

To a solution of methyl 2-amino-5-bromo-4-chlorobenzoate (1.0 g, 3.781mmol) in MeCN (35 mL) at RT, dry hydrogen chloride was addedcontinuously for 20 min. The resulting mixture was stirred at reflux for2 h. The mixture was allowed to cool to RT and poured into saturatedNaHCO₃ solution. The white solid was filtered, and the filtrate wasextracted with ethyl acetate. The filtrate cake and organic layer wascombined and dried over Na₂SO₄, concentrated in vacuo to afford thecrude product (1.62 g) as a white solid. ESI-MS m/z: 273.3 [M+H]⁺.

6-Bromo-4,7-dichloro-2-methylquinazoline

The mixture of 6-bromo-7-chloro-2-methylquinazolin-4-ol (500 mg, 1.828mmol) in 30 mL of SOCl₂ was stirred at reflux for 16 h. The mixture wasallowed to cool to RT and concentrated in vacuo. The residue waspurified through silica chromatography (5-10% ethyl acetate/petroleumether) to afford the desired product (180 mg, 34% yield) as a yellowsolid.

tert-Butyl4-(6-bromo-7-chloro-2-methylquinazolin-4-yl)piperazine-1-carboxylate

To a solution of tert-butyl piperazine-1-carboxylate (76 mg, 0.410 mmol)in i-PrOH (10 mL) at RT, 6-bromo-4,7-dichloro-2-methylquinazoline (60mg, 0.205 mmol) was added. The resulting mixture was stirred at refluxfor 40 min. The mixture was allowed to cool to RT and partitionedbetween water and ethyl acetate. The organic layer was washed withsaturated NaHCO₃ and brine, dried over Na₂SO₄ and concentrated. Theresidue was purified by flash column chromatography on silica gel (5%ethyl acetate/petroleum ether) to afford the desired product (53 mg, 59%yield) as a yellow solid.

1-(4-(7-Chloro-6-(4-chlorophenyl)-2-methylquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

The title compound was prepared from tert-butyl4-(6-bromo-7-chloro-2-methylquinazolin-4-yl)piperazine-1-carboxylate inthree steps according to the procedure described in Example 2. ¹H NMR(400 MHz, DMSO-d6) δ: 7.92 (s, 2H), 7.59 (m, 4H), 6.84-6.77 (dd, J=10.4,16.8 Hz, 1H), 6.17-6.36 (m, 1H), 5.74-5.71 (m, 1H), 3.85-3.72 (m, 8H),2.54 (s, 3H). ESI-MS m/z: 428.3 [M+H]⁺.

Example 16 Synthesis of1-acryloyl-4-(7-chloro-6-(4-chlorophenyl)-2-methylquinazolin-4-yl)piperazine-2-carbonitrile(56)

Compound 56 was prepared according to the general procedures of Method Mas described below:

1-tert-butyl 2-methyl4-(6-Bromo-7-chloro-2-methylquinazolin-4-yl)piperazine-1,2-dicarboxylate

To a solution of 6-bromo-4,7-dichloro-2-methylquinazoline (435 mg, 1.49mmol) and 1-tert-butyl 2-methyl piperazine-1,2-dicarboxylate (437 mg,1.79 mmol) in 1,4-dioxane (30 mL), DIEA (769 mg, 5.96 mmol) was added.The mixture was stirred at 80° C. for 1.5 h. The mixture was allowed tocool to RT and partitioned between water and ethyl acetate. The organiclayer was washed with brine, dried over Na₂SO₄ and concentrated. Theresidue was purified by flash column chromatography on silica gel (5-50%ethyl acetate/petroleum ether) to afford the desired product (224 mg,30% yield) as a yellow solid.

4-(6-Bromo-7-chloro-2-methylquinazolin-4-yl)-1-(tert-butoxycarbonyl)piperazine-2-carboxylicacid

To a solution of 1-tert-butyl 2-methyl4-(6-bromo-7-chloro-2-methylquinazolin-4-yl)piperazine-1,2-dicarboxylate(224 mg, 0.448 mmol) in THF (15 mL) and H₂O (5 mL), LiOH.H₂O (114 mg,2.690 mmol) was added and the resulting mixture was stirred at RT for 1h. The mixture was diluted with H₂O, acidified with HCl to adjust pH to4 and then extracted with ethyl acetate. The organic layer was washedwith brine, dried over Na₂SO₄ and concentrated in vacuo to afford thedesired product (211 mg, 97% yield) as a yellow solid.

tert-Butyl4-(6-bromo-7-chloro-2-methylquinazolin-4-yl)-2-carbamoylpiperazine-1-carboxylate

To a solution of4-(6-bromo-7-chloro-2-methylquinazolin-4-yl)-1-(tert-butoxycarbonyl)piperazine-2-carboxylicacid (221 mg, 0.435 mmol) and Et₃N (176 mg, 1.738 mmol) in THF (35 mL)at −5° C., ethyl chloroformate (51 mg, 0.465 mmol) was added. Themixture was stirred at −5° C. for 40 min and NH₃.H₂O (30%, 507 mg, 4.346mmol) was added. The resulting mixture was kept stirring for 5 min at 0°C. The mixture was partitioned between water and ethyl acetate. Theorganic layer was washed with brine, dried over Na₂SO₄ and concentrated.The residue was purified by flash column chromatography on silica gel(3% methanol/dichloromethane) to afford the desired product (179 mg, 85%yield) as a yellow solid. ESI-MS m/z: 484.3 [M+H]⁺.

tert-Butyl2-carbamoyl-4-(7-chloro-6-(4-chlorophenyl)-2-methylquinazolin-4-yl)piperazine-1-carboxylate

A mixture of tert-butyl4-(6-bromo-7-chloro-2-methylquinazolin-4-yl)-2-carbamoylpiperazine-1-carboxylate(179 mg, 0.371 mmol), (4-chlorophenyl)boronic acid (67 mg, 0.426 mmol),Pd(PPh₃)₄ (51 mg, 0.0445 mmol) and Na₂CO₃ (118 mg, 1.113 mmol) in1,4-dioxane (25 mL) was stirred at 85° C. for 16 h under argon. Themixture was allowed to cool to RT and concentrated in vacuo. The residuewas purified by flash column chromatography on silica gel (3%methanol/dichloromethane) to afford the desired product (181 mg, 95%yield) as a brown solid. ESI-MS m/z: 517.4 [M+H]⁺.

tert-Butyl4-(7-chloro-6-(4-chlorophenyl)-2-methylquinazolin-4-yl)-2-cyanopiperazine-1-carboxylate

To a solution of tert-butyl2-carbamoyl-4-(7-chloro-6-(4-chlorophenyl)-2-methylquinazolin-4-yl)piperazine-1-carboxylate(100 mg, 0.194 mmol) and Et₃N (78 mg, 0.775 mmol) in DCM (30 mL) at 0°C., TFAA (162 mg, 0.776 mmol) was added and the resulting mixture wasstirred at RT for 1 h. The reaction mixture was quenched with saturatedNaHCO₃ solution, and then extracted with dichloromethane. The organiclayer was washed with saturated NaHCO₃ solution and brine, dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by flashcolumn chromatographyon silica gel (petroleum ether/ethyl acetate=2:1)to afford the desired product (58 mg, 60% yield) as a yellow solid.ESI-MS m/z: 499.4[M+H]⁺.1-Acryloyl-4-(7-chloro-6-(4-chlorophenyl)-2-methylquinazolin-4-yl)piperazine-2-carbonitriletert-Butyl4-(7-chloro-6-(4-chlorophenyl)-2-methylquinazolin-4-yl)-2-cyanopiperazine-1-carboxylate(100 mg, 0.194 mmol) was dissolved in 20 mL of 20% HCl/Et₂O solution.The mixture was stirred at RT for 30 min and then concentrated in vacuoto yield a solid salt (44 mg, 87% yield). The above solid (44 mg, 0.101mmol) was dissolved in 25 mL of DCM with Et₃N (51 mg, 0.505 mmol). Themixture was cooled to 0° C. and then a solution of acryloyl chloride (10mg, 0.111 mmol) in dichloromethane (2 mL) was added. The resultingmixture was stirred at 0° C. for 40 min. The mixture was extracted withethyl acetate. The organic layer was washed with saturated NaHCO₃ andbrine, dried over Na₂SO₄ and concentrated. The residue was purified withsilica chromatography (petroleum ether/ethyl acetate=2:1) to afford thedesired product (24 mg, 52% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d6) δ: 8.01 (d, J=6.4 Hz, 2H), 7.63 (q, J=8.4, 20.4 Hz, 4H), 6.90(dd, J=10.4, 16.4 Hz, 1H), 6.30 (m, 1H), 5.68 (s, 1H), 4.60 (m, 1H),4.32 (m, 2H), 3.57 (m, 2H), 2.59 (s, 3H), 3.36 (m, 1H). ESI-MS m/z:453.3 [M+H]⁺.

Example 17 Synthesis of1-(4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)-2-(2-Hydroxyethyl)piperazin-1-yl)prop-2-en-1-one(62)

Compound 62 was prepared according to the general procedures of Method Aas described below:

Methyl 2-(3-oxopiperazin-2-yl)acetate

To a solution of dimethyl maleate (4.0 g, 27.78 mmol) in propan-2-ol (40mL) at RT, ethane-1,2-diamine (1.167 g, 27.78 mmol) was added. Theresulting mixture was stirred at 55° C. for 16 h and concentrated invacuo. The residue was washed by a mixture of ethyl acetate/petroleumether=1:1 to afford the desired product (2.8 g, 59% yield) as a whitesolid.

2-(Piperazin-2-yl)ethanol

To a solution of methyl 2-(3-oxopiperazin-2-yl)acetate (1.82 g, 10.58mmol) in THF (150 mL) at 0° C., LiAlH₄ (2.01 g, 52.9 mmol) was added.The resulting mixture was stirred at reflux for 16 h. Then the mixturewas cooled to RT. It was quenched with 10H₂O.Na₂SO₄ and filtered, washedwith ethyl acetate. The filtrated was dried over Na₂SO₄ and concentratedin vacuo to afford the desired product (674 mg, 49% yield) as a yellowoil.

2-(4-(7-Chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazin-2-yl)ethanol

A mixture of 4,7-dichloro-6-(4-chlorophenyl)quinazoline (150 mg, 0.48mmol), 2-(piperazin-2-yl)ethanol (187 mg, 1.44 mmol), Et₃N (0.33 mL, 2.4mmol), in 1,4-dioxane (5 mL) was stirred at 80° C. for 30 min. Themixture was allowed to cool to RT, quenched with saturated NaHCO₃solution and then extracted with ethyl acetate. The organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by flash column chromatography on silicagel (methanol/dichloroethane=1:30) to afford the desired product (121mg, 63% yield) as a colorless oil. ESI-MS m/z: 403.3 [M+H]⁺.

1-(4-(7-Chloro-6-(4-chlorophenyl)quinazolin-4-yl)-2-(2-hydroxyethyl)piperazin-1-yl)prop-2-en-1-one

To a solution of2-(4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazin-2-yl)ethanol(123 mg, 0.305 mmol), acrylic acid (24 mg, 0.336 mmol), BOP (270 mg,0.61 mmol) in DMF (5 mL) at −30° C., DIEA (157 mg, 1.22 mmol) was added.The resulting mixture was warmed to 0° C. over 1 h, quenched withsaturated NaHCO₃ solution, and then extracted with ethyl acetate. Theorganic layer was washed with saturated NaHCO₃ solution and brine, driedover Na₂SO₄ and concentrated in vacuo. The residue was purified byPre-HPLC to afford the desired product (16 mg, 12% yield) as alight-yellow oil. ¹H NMR (400 MHz, DMSO-d6) δ: 8.64 (s, 1H), 8.01 (s,1H), 7.99 (s, 1H), 7.64-7.57 (m, 4H), 6.89-6.78 (m, 1H), 6.17-6.13 (m,1H), 5.72 (dd, J=2.4, 10.4 Hz, 1H), 4.72-4.58 (m, 2H), 4.38-4.29 (m,4H), 4.06-3.99 (m, 1H), 3.67-3.60 (m, 2H), 1.79-1.68 (m, 2H). ESI-MSm/z: 457.4 [M+H]⁺.

Example 18 Synthesis of2-(1-acryloyl-4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazin-2-yl)acetonitrile(70)

Compound 70 was prepared according to the general procedures of Method Aas described below:

Dibenzyl 2-(2-hydroxyethyl)piperazine-1,4-dicarboxylate

To a solution of 2-(piperazin-2-yl)ethanol (2.0 g, 15.4 mmol) in THF (48mL), H₂O (32 mL) and saturated NaHCO₃ (32 mL) at 0° C., Cbz-Cl (5.5 g,32.3 mmol) was added dropwise. The mixture was stirred at 0° C. for 2 hand at RT for 16 h. The mixture was diluted with brine, extracted withdichloromethane. The organic layer was washed with brine, dried overNa₂SO₄ and concentrated. The residue was purified by flash columnchromatography on silica gel (25%-50% ethyl acetate/petroleum ether) toafford the desired product (1.454 g, 23% yield) as a colorless oil.ESI-MS m/z: 399.4 [M+H]⁺.

2-(1,4-Bis((benzyloxy)carbonyl)piperazin-2-yl)acetic acid

To a solution of dibenzyl 2-(2-hydroxyethyl)piperazine-1,4-dicarboxylate(515 mg, 1.294 mmol) in acetone (30 mL), Jones reagent (1.48 mL, 3.88mmol, 2.6 M) was added dropwise at 0° C., which was stirred at RT for 1h. The mixture was quenched with i-PrOH (2 mL) and filtered throughcelite. The filtrate was extracted with ethyl acetate. The organic layerwas washed with brine, dried over Na₂SO₄ and concentrated to afford thecrude product (545 mg) as a colorless oil. ESI-MS m/z: 413.2 [M+H]⁺.

Dibenzyl 2-(2-amino-2-oxoethyl)piperazine-1,4-dicarboxylate

To a solution of 2-(1,4-bis((benzyloxy)carbonyl)piperazin-2-yl)aceticacid (545 mg, 1.323 mmol) and Et₃N (535 mg, 5.292 mmol) in THF (20 mL),ethyl chloroformate (154 mg, 1.415 mmol) was added at −10° C. andstirred at this temperature for 40 min. Then the mixture was addedNH₃.H₂O (1.984 g, 15.87 mmol) at −10° C. and stirred for 20 min at −10°C. The mixture was partitioned between water and ethyl acetate. Theorganic layer was washed with brine, dried over Na₂SO₄ and concentrated.The residue was purified by flash column chromatography on silica gel(2% methanol/dichloromethane) to afford the desired product (393 mg, 72%yield) as a colorless oil. ESI-MS m/z: 412.3 [M+H]⁺.

2-(Piperazin-2-yl)acetamide

A mixture of dibenzyl 2-(2-amino-2-oxoethyl)piperazine-1,4-dicarboxylate(385 mg, 0.937 mmol), Pd/C (10%, 40 mg) and MeOH (30 mL) was stirred at40° C. for 2.5 h under H₂ (1 atm). The mixture was filtered throughcelite and concentrated to afford the crude product (188 mg) as acolorless oil.

2-(4-(7-Chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazin-2-yl)acetamide

A mixture of 4,7-dichloro-6-(4-chlorophenyl)quinazoline (313 mg, 1.315mmol), 2-(piperazin-2-yl)acetamide (188 mg, 1.315 mmol), DIEA (848 mg,6.575 mmol) and 1,4-dioxane (30 mL) at 100° C. for 5 h. The mixture wasallowed to cool to RT and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (5-20%methanol/dichloromethane) to afford the desired product (78 mg, 14%yield) as a brown solid. ESI-MS m/z: 417.3 [M+H]⁺.

2-(1-Acryloyl-4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazin-2-yl)acetamide

A mixture of2-(4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazin-2-yl)acetamide(78 mg, 0.1875 mmol), Et₃N (76 mg, 0.750 mmol) and dichloromethane (30mL) at 0° C., a solution of acryloyl chloride (21 mg, 0.225 mmol) indichloromethane (2 mL) was added dropwise. The resulting mixture wasstirred at 0° C. for 40 min. The mixture was quenched with saturatedNaHCO₃ and extracted with ethyl acetate. The organic layer was washedwith brine, dried over Na₂SO₄ and concentrated. The residue was purifiedwith column chromatography on silica gel (2.5-4% methanol indichloromethane) to afford the desired product (32 mg, 36% yield) as awhite solid. ¹H NMR (400 MHz, DMSO-d6) δ: 8.74 (s, 1H), 8.07 (s, 1H),7.80 (s, 1H), 7.50-7.42 (dd, J=8.8, 14.4 Hz, 1H), 6.79-6.24 (m, 3H),5.83 (m, 1H), 5.36-5.14 (m, 2H), 4.72-4.49 (m, 2H, 4.32 (m, 1H),3.99-3.49 (m, 3H), 3.07-2.44 (m, 3H). ESI-MS m/z: 470.2 [M+H]⁺.

2-(1-Acryloyl-4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazin-2-yl)acetonitrile

To a solution of2-(1-acryloyl-4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazin-2-yl)acetamide(25 mg, 0.0533 mmol) and Et₃N (27 mg, 0.267 mmol) in DCM (10 mL) at 0°C., TFAA (46 mg, 0.214 mmol) and the resulting mixture was stirred at RTfor 20 min. The reaction mixture was quenched with saturated NaHCO₃solution, and then extracted with dichloromethane. The organic layer waswashed with saturated NaHCO₃ solution and brine, dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash columnchromatographyon silica gel (2.5% methanol in dichloromethane) to affordthe desired product (21 mg, 87% yield) as a white solid. ¹H NMR (400MHz, DMSO-d6) δ: 8.67 (s, 1H), 8.06 (m, 2H), 7.70 (s, 4H), 6.88 (m, 1H),6.20 (d, J=10.0 Hz, 1H), 5.76 (s, 1H), 4.97 (m, 1H), 4.30 (m, 4H), 3.75(m, 2H), 2.99 (m, 2H). ESI-MS m/z: 453.3 [M+H]⁺.

Example 19 Synthesis of4-(4-acryloyl-3-cyanopiperazin-1-yl)-7-chloroquinazoline-6-carbonitrile(53)

Compound 53 was prepared according to the general procedures of Method Bas described below:

1-tert-Butyl 2-methyl4-(6-bromo-7-chloroquinazolin-4-yl)piperazine-1,2-dicarboxylate

A mixture of 6-bromo-4,7-dichloroquinazoline (300 mg, 1.08 mmol),tert-butyl methyl piperazine-1,2-dicarboxylate (395 mg, 1.62 mmol), DIEA(836 mg, 6.48 mmol) in 1,4-dioxane (8 mL) was stirred at 80° C. for 1 h.The mixture was allowed to cool to RT, quenched with saturated NaHCO₃solution and then extracted with ethyl acetate. The organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by flash column chromatography on silicagel (ethyl acetate/petroleum ether=1:5) to afford the desired product(367 mg, 70% yield) as a white solid.

1-(tert-Butoxycarbonyl)-4-(6-bromo-7-chloroquinazolin-4-yl)piperazine-2-carboxylicacid

To a solution of 1-tert-butyl 2-methyl4-(6-bromo-7-chloroquinazolin-4-yl)piperazine-1,2-dicarboxylate (100 mg,0.206 mmol) in THF (2 mL), MeOH (2 mL) and water (2 mL), LiOH.H₂O (165mg, 4.12 mmol) was added and the resulting mixture was stirred at RT for1 h. The mixture was washed with 20% ethyl acetate/petroleum ether. Theaqueous layer was acidified with aqueous HCl (1 N) to adjust pH to 5 andextracted with ethyl acetate. The organic layer was dried over MgSO4,filtered, and concentrated in vacuo to afford the desired product (65mg, 67% yield).

tert-Butyl4-(6-bromo-7-chloroquinazolin-4-yl)-2-carbamoylpiperazine-1-carboxylate

To a mixture of1-(tert-butoxycarbonyl)-4-(6-bromo-7-chloroquinazolin-4-yl)piperazine-2-carboxylicacid (65 mg, 0.14 mmol), Et₃N (0.11 mL, 0.77 mmol) in THF (4 mL) and DMF(2 mL) at 0° C., ethyl chloroformate (83 mg, 0.77 mmol) was added. Theresulting mixture was stirred at 0° C. for 1 h and NH₃.H₂O (1 mL, 15 N)was added. Then the mixture was warmed to RT and stirred for another 1h. It was quenched with saturated NaHCO₃ solution and then extractedwith ethyl acetate. The organic layer was washed with brine, dried overNa₂SO₄, filtered and concentrated in vacuo to afford the crude product(77 mg) as a yellow solid. ESI-MS m/z: 471.4 [M+H]⁺.

tert-Butyl2-carbamoyl-4-(7-chloro-6-cyanoquinazolin-4-yl)piperazine-1-carboxylate

A mixture of tert-butyl4-(6-bromo-7-chloroquinazolin-4-yl)-2-carbamoylpiperazine-1-carboxylate(200 mg, 0.43 mmol), PdCl₂(dppf) (31 mg, 0.043 mmol), Zn(CN)₂ (80 mg,0.68 mmol) and DMF (20 mL) was stirred at reflux for 5 h. The mixturewas allowed to cool to room temperature, and partitioned between ethylacetate and water. The organic layer was washed with brine, dried overNa₂SO₄ and concentrated. The residue was purified by flash columnchromatography on silica gel (1-2% methanol/dichloromethane) to affordthe desired product (140 mg, 79% yield) as a solid. ESI-MS m/z: 417.3[M+H]⁺.

4-(7-Chloro-6-cyanoquinazolin-4-yl)piperazine-2-carboxamide

A solution oftert-butyl2-carbamoyl-4-(7-chloro-6-cyanoquinazolin-4-yl)piperazine-1-carboxylate(140 mg, 0.34 mmol) in dichloromethane (20 mL) at RT, TFA (2 mL) wasadded. The resulting mixture was stirred at RT for 2 h. The mixture wasconcentrated in vacuo to afford the crude product (100 mg) which wasused directly in the next step without further purification.

1-Acryloyl-4-(7-chloro-6-cyanoquinazolin-4-yl)piperazine-2-carboxamide

A mixture of 4-(7-chloro-6-cyanoquinazolin-4-yl)piperazine-2-carboxamide(100 mg, 0.32 mmol), Et₃N (96 mg, 0.96 mmol) in dichloromethane (10 mL)at 0° C., acryloyl chloride (35 mg, 0.384 mmol) was added. The resultingmixture was stirred at RT for 0.5 h, poured into water and thenextracted with dichloromethane. The organic layer was washed with brine,dried over Na₂SO₄ and concentrated. The residue was purified by flashcolumn chromatography on silica gel (1-2% methanol/dichloromethane) toafford the desired product (50 mg, 43% yield) as a solid. ESI-MS m/z:371.3 [M+H]⁺.

4-(4-Acryloyl-3-cyanopiperazin-1-yl)-7-chloroquinazoline-6-carbonitrile

A mixture of1-acryloyl-4-(7-chloro-6-cyanoquinazolin-4-yl)piperazine-2-carboxamide(50 mg, 0.14 mmol) and Et₃N (82 mg, 0.81 mmol) in DCM (10 mL) at RT,trifluoroacetic anhydride (117.6 mg, 0.56 mmol) was added. The resultingmixture was stirred at RT for 0.5 h and poured into water and thenextracted with dichloromethane. The organic layer was washed with brine,dried over Na₂SO₄ and concentrated. The residue was purified by flashcolumn chromatography on silica gel (1-3% methanol/dichloromethane) toafford the desired product (15 mg, 32% yield). ¹H NMR (400 MHz, DMSO-d6)δ: 8.79 (s, 1H), 8.77 (s, 1H), 8.16 (s, 1H), 6.92-6.85 (m, 1H),6.32-6.28 (m, 1H), 5.91-5.88 (m, 1H), 5.68 (s, 1H), 4.73-4.70 (d, J=14Hz, 1H), 4.46-4.43 (d, J=13.2 Hz, 1H), 4.25-4.22 (d, J=12.8 Hz, 1H),3.82-3.74 (m, 2H), 3.59-3.56 (m, 1H). ESI-MS m/z: 353.2 [M+H]⁺.

Example 20 Synthesis of1-acryloyl-4-(7-chloro-6-cyclopropylquinazolin-4-yl)piperazine-2-carbonitrile(55)

Compound 55 was prepared according to the general procedures of Method Bas described below:

tert-Butyl2-carbamoyl-4-(7-chloro-6-cyclopropylquinazolin-4-yl)piperazine-1-carboxylate

A mixture of tert-butyl4-(6-bromo-7-chloroquinazolin-4-yl)-2-carbamoylpiperazine-1-carboxylate(200 mg, 0.414 mmol), cyclopropylboronic acid (44 mg, 0.51 mmol),K₃PO₄.3H₂O (270 mg, 1.272 mmol), Pd(OAc)₂ (18 mg, 0.08 mmol) andtricyclohexyl phosphine (22 mg, 0.08 mmol) in toluene (10 mL) and water(1 mL) was stirred at reflux under argon for 16 h. The solvent wasremoved, and the residue was purified by flash column chromatography onsilica gel (dichloromethane/methanol=50:1) to afford the desired product(100 mg, 56% yield) as a solid. ESI-MS m/z: 432.4 [M+H]⁺.

Acryloyl-4-(7-chloro-6-cyclopropylquinazolin-4-yl)piperazine-2-carboxamide

The title compound was prepared from tert-butyl2-carbamoyl-4-(7-chloro-6-cyclopropylquinazolin-4-yl)piperazine-1-carboxylatein two steps following the procedure described in Example 1.

Acryloyl-4-(7-chloro-6-cyclopropylquinazolin-4-yl)piperazine-2-carboxamide

To a solution of1-acryloyl-4-(7-chloro-6-cyclopropylquinazolin-4-yl)piperazine-2-carboxamide(17 mg, 0.044 mmol) and Et₃N (18 mg, 0.176 mmol) in DCM (5 mL) at 0° C.,TFAA (18 mg, 0.088 mmol) was added and the resulting mixture was stirredat RT for 1 h. The reaction mixture was quenched with saturated NaHCO₃solution, and then extracted with dichloromethane. The organic layer waswashed with saturated NaHCO₃ solution and brine, dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash columnchromatographyon silica gel (dichloromethane/methanol=50:1) to affordthe desired product (10 mg, 62% yield) as a solid. ¹H NMR (400 MHz,CDCl3) δ: 8.8 (s, 1H), 8.0 (s, 1H), 7.7 (s, 1H), 6.6 (dd, J=10.0, 16.4Hz, 1H), 6.5 (d, J=16.4 Hz, 1H), 6.0 (dd, J=2.0, 10.4 Hz, 1H), 6.0-5.9(m, 1H), 4.4 (dd, J=2, 13.2 Hz, 1H), 4.3-4.1 (m, 2H), 3.9-3.8 (m, 1H),3.3-3.1 (m, 2H), 2.4-2.3 (m, 1H), 1.2-1.1 (m, 2H), 1.0-0.9 (m, 2H).ESI-MS m/z: 368.3 [M+H]⁺.

Example 21 Synthesis of(S)-1-acryloyl-4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazine-2-carboxamide(54)

Compound 54 was prepared according to the general procedures of Method Aas described below:

(S)-Methyl piperazine-2-carboxylate hydrochloride

A mixture of (S)-tert-butyl methyl piperazine-1,3-dicarboxylate (366 mg,1.5 mmol) and HCl in MeOH (20 mL, 2.9 M) was stirred at RT for 1 h. Themixture was concentrated in vacuo to yield the crude product (270 mg) asa yellow solid which was used directly in next step without furtherpurification.

(S)-1-tert-Butyl 2-methyl4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazine-1,2-dicarboxylate

To the mixture of above obtained crude (S)-methylpiperazine-2-carboxylate hydrochloride,4,7-dichloro-6-(4-chlorophenyl)quinazoline (310 mg, 1 mmol), DIEA (1.29g, 10 mmol) and 1,4-dioxane (20 mL) was stirred for 1 h at 80° C. Thenmixture was cooled to RT and di-tert butyl dicarbonate (327 mg, 1.5mmol) was added. The mixture was stirred for 16 h and quenched withsaturated NaHCO₃ solution and then extracted with ethyl acetate. Theorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (methanol/dichloroethane=1:50) to affordthe desired product (300 mg, 58% yield, 2 steps) as a solid oil. ESI-MSm/z: 517.5 [M+H]⁺.

(S)-1-(tert-Butoxycarbonyl)-4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazine-2-carboxylicacid

To a solution of (S)-1-tert-butyl 2-methyl4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazine-1,2-dicarboxylate(300 mg, 0.58 mmol) in mixture of 1:1 tetrahydrofuran and water (20 mL)at RT, LiOH.H₂O (49 mg, 1.16 mmol) were added and the resulting mixturewas stirred for 1 h and then acidified with aqueous HCl (1 N) to adjustthe pH to 3-5. The mixture was extracted with ethyl acetate. Thecombined organic layer was washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated in vacuo to afford the crude product(230 mg) which was used directly in the next step without furtherpurification.

(S)-tert-Butyl2-carbamoyl-4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazine-1-carboxylate

To a mixture of(S)-1-(tert-butoxycarbonyl)-4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazine-2-carboxylicacid (230 mg, 0.46 mmol), Et₃N (139 mmg, 1.37 mmol) in THF (5 mL) at 0°C., ethyl chloroformate (148 mg, 1.37 mmol) was added. The resultingmixture was stirred at 0° C. for 1 h, then Ammonium hydroxide (1 mL, 15N) was added and kept stirring for another 1 h at RT. The mixture wasextracted with ethyl acetate dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (dichloromethane/methanol=50:1) to affordthe desired product (150 mg, 65% yield) as a solid. ESI-MS m/z: 502.4[M+H]⁺.

(S)-1-Acryloyl-4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazine-2-carboxamide

The title compound was prepared from (S)-tert-butyl2-carbamoyl-4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazine-1-carboxylatein2 steps according to the procedure described in Example 1. ¹H NMR (400MHz, DMSO-d6) δ: 8.7 (s, 1H), 8.3 (d, J=8.0 Hz, 1H), 8.0 (s, 1H),7.8-7.5 (m, 5H), 7.4-7.2 (m, 1H), 6.9-6.6 (m, 1H), 6.2 (d, J=2.4, 17.6Hz, 1H), 5.8-5.7 (m, 1H), 5.0-4.8 (m, 1H), 4.7 (d, J=13.2 Hz, 1H),4.2-4.0 (m, 2H), 3.9-3.8 (m, 1H), 3.7-3.5 (m, 1H), 3.5-3.4 (m, 1H).ESI-MS m/z: 456.3 [M+H]⁺.

Example 22 Synthesis of(S)-1-acryloyl-4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazine-2-carbonitrile(59)

Compound 59 was prepared according to the general procedures of Method Aas described below:

(S)-1-Acryloyl-4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazine-2-carbonitrile

To a solution of(S)-1-acryloyl-4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazine-2-carboxamide(23 mg, 0.05 mmol) and Et₃N (20 mg, 0.2 mmol) in DCM (5 mL) at 0° C.,trifluoroacetic anhydride (21 mg, 0.1 mmol) and the resulting mixturewas stirred at RT for 1 h. The reaction mixture was quenched withsaturated NaHCO₃ solution, and then extracted with dichloromethane. Theorganic layer was washed with saturated NaHCO₃ solution and brine, driedover Na₂SO₄ and concentrated in vacuo. The residue was purified by flashcolumn chromatographyon on silica gel (dichloromethane/methanol=50:1) toafford the desired product (15 mg, 68% yield) as a solid. ¹H NMR (400MHz, DMSO-d6) δ: 8.7 (s, 1H), 8.1 (s, 1H), 8.0 (s, 1H), 7.5 (m, 4H), 6.8(dd, J=10.4, 16.4 Hz, 1H), 6.3 (dd, J=2.0, 17.2 Hz, 1H), 5.8 (dd, J=2.0,10.8 Hz, 1H), 5.7 (m, 1H), 4.6 (d, J=14.0 Hz, 3H), 4.3 (m, 2H), 3.6 (m,2H). ESI-MS m/z: 438.3 [M+H]⁺.

Example 23 Synthesis of(S)-1-(4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)-2-(hydroxymethyl)piperazin-1-yl)prop-2-en-1-one(63)

Compound 63 was prepared according to the general procedures of Method Aas described below:

(S)-tert-Butyl4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylate

To a solution of (S)-1-tert-butyl 2-methyl4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazine-1,2-dicarboxylate(200 mg, 0.387 mmol) in EtOH (10 mL) was added CaCl₂ (215 mg, 1.933mmol) and NaBH₄ (74 mg, 1.933 mmol) at 0° C. The mixture was stirred atRT for 16 h. The mixture was filtered, and washed by ethylanol. Themixture was concentrated in vacuo, and the residue was purified by flashcolumn chromatography on silica gel (dichloromethane/methanol=50:1) toafford the desired product (80 mg, 42% yield) as a solid. ESI-MS m/z:489.4 [M+H]⁺.

1-((S)-4-(7-Chloro-6-(4-chlorophenyl)quinazolin-4-yl)-2-(hydroxymethyl)piperazin-1-yl)prop-2-en-1-one

The title compound was prepared from (S)-tert-butyl4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)-2-(hydroxymethyl)piperazine-1-carboxylatein two steps according to the procedure described in Example 13. ¹H NMR(400 MHz, DMSO-d6) δ: 8.7 (s, 1H), 8.3-8.1 (m, 1H), 8.0 (s, 1H), 7.7-7.5(m, 4H), 6.8 (dd, J=10.4, 16.4 Hz, 1H), 6.1 (d, J=16 Hz, 1H), 5.8 (dd,J=2, 10.4 Hz, 1H), 5.1-4.9 (m, 1H), 4.3-4.1 (m, 4H), 4.2 (m, 2H),3.7-3.5 (m, 4H). ESI-MS m/z: 443.3 [M+H]⁺.

Example 24 Synthesis of1-(4-(6-chloro-7-phenylquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one(67)

Compound 67 was prepared according to the general procedures of Method Bas described below:

7-Bromo-6-chloroquinazolin-4-ol

To a solution of 2-amino-4-bromo-5-chlorobenzoic acid (500 mg, 2 mmol)in EtOH (20 mL) at RT, formamidine acetate (620 mg, 6 mmol) was added.The mixture was reflux for 16 hour. The mixture was concentrated invacuo, and the residue was washed by saturated NaHCO₃ aqueous solution,and a mixture of ethyl acetate/petroleum ether=1:2. The solid was driedin vacuo to get the product (520 mg, 100% yield) which was used directlyin next step without further purification. ESI-MS m/z: 259.0 [M+H]⁺.

7-Bromo-4,6-dichloroquinazoline

To a solution of 7-bromo-6-chloroquinazolin-4-ol (520 mg, 2 mmol) inthionyl chloride (15 mL) was added one drop of DMF. The mixture wasreflux for 16 h. The mixture was concentrated in vacuo, the residue wasused directly in next step without further purification.

1-(4-(6-Chloro-7-phenylquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

The title compound was prepared from 7-bromo-4,6-dichloroquinazoline infour steps according to the procedure described in Example 2. ¹H NMR(400 MHz, DMSO) δ: 8.7 (s, 1H), 8.2 (s, 1H), 7.8 (s, 1H), 7.6-7.4 (m,5H), 6.85 (dd, J=10.8, 16.8 Hz, 1H), 6.2 (d, J=16.8 Hz, 1H), 5.75 (d,J=10 Hz, 1H), 3.9-3.7 (m, 8H). ESI-MS m/z: 379.3 [M+H]⁺.

Example 25 Synthesis of1-(4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)-2-((dimethylamino)methyl)piperazin-1-yl)prop-2-en-1-one(60)

Compound 60 was prepared according to the general procedures of Method Aas described below:

di-tert-Butyl 2-(dimethylcarbamoyl)piperazine-1,4-dicarboxylate

A mixture of 1,4-bis(tert-butoxycarbonyl)piperazine-2-carboxylic acid (5g, 15.13 mmol), dimethylamine hydrochloride (1.3 g, 15.13 mmol), EDCI(4.3 g, 22.7 mmol), HOBt (3.1 g, 22.7 mmol) and DMF (100 mL) at 0° C.,Et₃N (4.6 g, 45.39 mmol) was added. The mixture was then warmed to RTand kept stirring for 2 h. The reaction mixture was poured into water,extracted with ethyl acetate, the combined organic layer was washed withNaHCO₃ solution, brine and dried over Na₂SO₄ and concentrated. Theresidue was washed with petroleum ether to afford the desired product(3.64 g, 67% yield).

N,N-Dimethylpiperazine-2-carboxamide dihydrochloride

A mixture of the above obtained crude of di-tert-butyl2-(dimethylcarbamoyl)piperazine-1,4-dicarboxylate, HCl in MeOH (50 mL,2.9 M) was stirred at RT for 1 h, evaporated the solvent to afford thecrude product (2.4 g).

N,N-Dimethyl-1-(piperazin-2-yl)methanamine

A mixture of the above obtained crude ofN,N-dimethylpiperazine-2-carboxamide dihydrochloride (2.4 g, 10.43 mmol)and THF (50 mL) at −40° C., LiAlH₄ (1.6 g, 41.73 mmol) was added slowly.The mixture was heated to reflux for 3 h and cooled to RT. It wasquenched with 10H₂O.Na₂SO₄ and filtered, washed with ethyl acetate. Thefiltrated was dried over Na₂SO₄ and concentrated in vacuo to afford thedesired product (693 mg, 47% yield).

1-(4-(7-Chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazin-2-yl)-N,N-dimethylmethanamine

A mixture of N,N-dimethyl-1-(piperazin-2-yl)methanamine (200 mg, 0.68mmol), 4,7-dichloro-6-(4-chlorophenyl)quinazoline (111 mg, 0.77 mmol),DIEA (397 mg, 3.08 mmol) and dioxane (10 mL) was stirred at 80° C. for30 min. The mixture was allowed to cool to RT, quenched with saturatedNaHCO₃ solution and then extracted with ethyl acetate. The organic layerwas washed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by flash column chromatography on silicagel (methanol/dichloroethane=1:20) to afford the desired product (78 mg,30% yield). ESI-MS m/z: 416.3 [M+H]⁺.

1-(4-(7-Chloro-6-(4-chlorophenyl)quinazolin-4-yl)-2-((dimethylamino)methyl)piperazin-1-yl)prop-2-en-1-one

A mixture of1-(4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazin-2-yl)-N,N-dimethylmethanamine(78 mg, 0.19 mmol), Et₃N (58 mg, 0.57 mmol) and dichloromethane (15 mL)at 0° C., acryloyl chloride (20 mg, 0.22 mmol) was added. The reactionwas stirred at RT for 30 min and quenched with water, extracted withdichloromethane. The organic layer was washed with water and brine,anhydrous sodium sulfate, filtered and concentrated in vacuo. Theresidue was purified by flash column chromatography on silica gel(dichloromethane/methanol=30:1) to afford the desired product (32 mg,36% yield). ¹H NMR (400 MHz, DMSO-d6) δ: 8.70 (s, 1H), 8.57-8.56 (bs,1H), 8.03 (s, 1H), 7.61-7.53 (m, 4H), 6.83-6.80 (m, 1H), 6.17-6.13 (m,1H), 5.75-5.72 (m, 1H), 4.76-4.74 (m, 0.5H), 4.70-4.57 (m, 1H),4.36-3.29 (m, 2H), 4.11-4.08 (m, 0.5H), 3.46 (m, 1H), 3.27-3.11 (m, 2H),2.93-2.84 (m, 1H), 1.99-1.94 (m, 1H), 1.87 (s, 6H). ESI-MS m/z: 470.4[M+H]⁺.

Example 26 Synthesis of1-acryloyl-4-(6-chloroisoquinolin-1-yl)piperazine-2-carbonitrile (61)

Compound 61 was prepared according to the general procedures of Method Das described below:

6-Chloroisoquinoline 2-oxide

To a stirred solution 6-chloroisoquinoline (1.0 g, 6.1 mmol) indichloromethane (20 mL) at RT, 3-chlorobenzoperoxoic acid (1.57 g, 9.2mmol) was added. The reaction mixture was stirred at RT for 2 h. Theprecipitate was filtered off and washed with dichloromethane, thefiltrate was washed twice with NaHCO₃ solution. The organic layer wasdried with Na₂SO₄ and concentrated in vacuo to afford the desiredproduct (1.05 g, 96% yield) as a white solid. ESI-MS m/z: 180.2 [M+H]⁺.

1,6-Dichloroisoquinoline

A mixture of 6-chloroisoquinoline 2-oxide (1.0 g, 5.58 mmol) and POCl₃(10 mL) was heated to reflux for 4 h. After cooled down to RT, thereaction mixture was poured into ice-water, and extracted withdichloromethane. The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo to afford the desired crude productwhich was used in the next step without further purification.

4-(6-Chloroisoquinolin-1-yl)piperazine-2-carboxamide

To a stirred solution of 1,6-dichloroisoquinoline (500 mg, 2.56 mmol) inDMSO (5 mL) at RT, piperazine-2-carboxamide (425.6 mg, 2.56 mmol) andK₂CO₃ (1.05 g, 7.68 mmol). The reaction mixture was heated at 80° C. for5 h. The reaction mixture was diluted with ethyl acetate and washed withbrine. The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (ethyl acetate/petroleum ether=1:5) toafford the desired product (80 mg, 12% yield). ESI-MS m/z: 291[M+H]⁺.

Acryloyl-4-(6-chloroisoquinolin-1-yl)piperazine-2-carboxamide

To a mixture of 4-(6-chloroisoquinolin-1-yl)piperazine-2-carboxamide (50mg, 0.172 mmol), triethylamine (52.1 mg, 0.51 mmol) in dichloromethane(20 mL), acryloyl chloride (15.6 mg, 0.172 mmol) in dichloromethane (1mL) was added dropwise.

The reaction mixture was stirred at RT for 30 min, poured into water,and extracted with dichloromethane. The organic layer was washed withwater and brine, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography on silica gel(dichloromethane/methanol=100:1) to afford the desired product (45 mg,76.3% yield). ESI-MS m/z: 345 [M+H]⁺.

Acryloyl-4-(6-chloroisoquinolin-1-yl)piperazine-2-carbonitrile

To a mixture of1-acryloyl-4-(6-chloroisoquinolin-1-yl)piperazine-2-carboxamide (40 mg,0.116 mmol), triethylamine (46.8 mg, 0.46 mmol) in DCM (5 mL) at 0° C.,trifluoroacetic anhydride (50 mg, 0.233 mmol) was added. The reactionmixture was warmed to RT over 1 h, poured into water and extracted withdichloromethane. The organic layer was washed with water and brine,dried over Na₂SO₄ and concentrated in vacuo. The residue was purified byflash column chromatography on silica gel(dichloromethane/methanol=100:1) to afford the desired product (20 mg,53% yield). ¹H NMR (400 MHz, DMSO-d6) δ: 8.25 (m, 1H), 8.22 (m, 1H),8.11 (s, 1H), 7.71 (m, 1H), 7.52 (m, 1H), 6.96 (dd, J=10.5, 16.9 Hz,1H), 6.32 (dd, J=1.7, 16.7 Hz, 1H), 5.90 (dd, J=1.7, 16.7 Hz, 1H), 5.79(m, 1H), 4.34 (m, 1H), 3.99 (m, 1H), 3.79 (m, 1H), 3.66 (m, 1H), 3.16(m, 1H), 2.97 (m, 1H). ESI-MS m/z: 327 [M+H]⁺.

Example 27 Synthesis of(E)-4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)-1-(4-(dimethylamino)but-2-enoyl)piperazine-2-carbonitrile(66)

Compound 66 was prepared according to the general procedures of Method Aas described below:

4-(7-Chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazine-2-carboxamide

A mixture of 4,7-dichloro-6-(4-chlorophenyl)quinazoline (769 mg, 2.48mmol), piperazine-2-carboxamide dihydrochloride (498 mg, 2.48 mmol),DIPEA (3.2 g, 24.8 mmol) and 1,4-dioxane (20 mL) was stirred at 80° C.for 16 h. The mixture was allowed to cool to RT, quenched with saturatedNaHCO₃ solution and then extracted with ethyl acetate. The organic layerwas washed with brine, dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by flash column chromatography on silicagel (methanol/dichloroethane=1:20) to afford the desired product (486mg, 48.7% yield).

(E)-4-(7-Chloro-6-(4-chlorophenyl)quinazolin-4-yl)-1-(4-(dimethylamino)but-2-enoyl)piperazine-2-carboxamide

To a mixture of4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)piperazine-2-carboxamide(100 mg, 0.26 mmol), BOP (256.6 mg, 0.58 mmol),(E)-4-(dimethylamino)but-2-enoic acid (48 mg, 0.58 mmol) indichloromethane (10 ml) at RT, DIEA (108.6 mg, 0.78 mmol) was added. Themixture was stirred for 30 min, extracted with ethyl acetate. Theorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (methanol/dichloroethane=1:10) to affordthe desired product (50 mg, 39% yield). ESI-MS m/z: 513.3 [M+H]⁺

(E)-4-(7-Chloro-6-(4-chlorophenyl)quinazolin-4-yl)-1-(4-(dimethylamino)but-2-enoyl)piperazine-2-carbonitrile

To a solution of(E)-4-(7-chloro-6-(4-chlorophenyl)quinazolin-4-yl)-1-(4-(dimethylamino)but-2-enoyl)piperazine-2-carboxamide(50 mg, 0.10 mmol) and Et₃N (0.05 mL, 0.40 mmol) in DCM (10 mL) at 0°C., TFAA (51 mg, 0.20 mmol) and the resulting mixture was stirred at RTfor 1 h. The reaction mixture was quenched with saturated NaHCO₃solution, and then extracted with dichloromethane. The organic layer waswashed with saturated NaHCO₃ solution and brine, dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (dichloromethane/methanol=20:1) to affordthe desired product (14 mg, 29% yield) as a solid. ¹H NMR (400 MHz,DMSO-d6) δ: 8.76 (s, 1H), 8.08 (d, J=16 Hz, 2H), 7.61 (dd, J=8, 24 Hz,4H), 6.78-6.72 (m, 2H), 5.67 (s, 1H), 4.62 (d, J=14.4 Hz, 1H), 4.36-4.26(m, 2H), 3.63 (d, J=12.4 Hz, 1H), 3.21 (s, 2H), 3.03 (d, J=6.4 Hz, 2H),2.26 (s, 1H). ESI-MS m/z: 495.4 [M+H]⁺.

Example 28 Synthesis of1-(4-(7-(2-fluorophenyl)-6-hydroxyquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 28 is an exemplary preparation according to General SyntheticMethod B.

1-Bromo-2-fluoro-4-methyl-5-nitrobenzene

HNO₃ (9 mL) was added into a solution of1-bromo-2-fluoro-4-methylbenzene (5.35 g, 28.30 mmol) in H₂SO₄ (25 mL)while it was kept at −20° C. and the resulting mixture was stirred at 0°C. for 10 min. The mixture was poured into ice-water and extracted withethyl acetate. The organic layer was washed with saturated NaHCO₃aqueous solution and brine, dried over Na₂SO₄ and concentrated in vacuoto yield the product as a yellow solid (5.3 g, 80% yield).

1-Bromo-2-methoxy-4-methyl-5-nitrobenzene

Na (351 mg, 15.28 mmol) was added into CH₃OH (20 mL) and the resultingmixture was stirred at 0° C. for 30 min.1-Bromo-2-fluoro-4-methyl-5-nitrobenzene (3.25 g, 13.89 mmol) was addedto the mixture and then stirred at 30° C. for 2 h. The solvent wasremoved and the residue was dissolved in H₂O, extracted with ethylacetate. The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (ethyl acetate/petroleum ether=1:50) to yield the productas a white solid (3.0 g, 87.8% yield).

4-Bromo-5-methoxy-2-nitrobenzaldehyde

A mixture of 1-bromo-2-methoxy-4-methyl-5-nitrobenzene (3.7 g, 15.04mmol) and DMF-DMA (5.41 g, 45.12 mmol) in DMF (40 mL) was stirred at140° C. for 16 h. The mixture was allowed to cool to RT and concentratedin vacuo. The residue was dissolved in DMF (40 mL) and added into asolution of NaIO₄ (19.22 g, 90.24 mmol) in DMF (120 mL) and H₂O (30 mL)at 0° C. The resulting mixture was stirred at 30° C. for 16 h, quenchedwith H₂O, and then extracted with ethyl acetate. The organic layer waswashed with brine, dried over Na₂SO₄ and concentrated in vacuo, theresidue was purified by column chromatography on silica gel(acetate/petroleum ether=1:20) to yield the product as an off-whitesolid (1.52 g, 38.9% yield).

4-Bromo-5-methoxy-2-nitrobenzoic acid

A mixture of 4-bromo-5-methoxy-2-nitrobenzoic acid (1.52 g, 5.84 mmol)and KMnO₄ (5.53 g, 35.04 mmol) in CH₃CN (40 mL) was stirred at refluxfor 2 h. The mixture was allowed to cool to RT, quenched with H₂O,adjusted pH to 3-4 with 1N HCl, and then extracted with ethyl acetate.The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to yield the product as an off-white solid (1.24g, 77.4% yield).

methyl 4-bromo-5-methoxy-2-nitrobenzoate

A mixture of 4-bromo-5-methoxy-2-nitrobenzoic acid (1.24 g, 4.52 mmol)and SOCl₂ (5 mL) in CH₃OH (10 mL) was stirred at reflux for 2 h, Thensolvent was removed and the residue was dissolved in H₂O, extracted withethyl acetate. The organic layer was washed with brine, dried overNa₂SO₄ and concentrated to yield the product as an off-white solid (1.3g, 99% yield).

Methyl 2-amino-4-bromo-5-methoxybenzoate

A mixture of methyl 4-bromo-5-methoxy-2-nitrobenzoate (1.3 g, 4.48 mmol)and Fe (1.25 g, 22.4 mmol) in acetic acid (10 mL) and H₂O (10 mL) wasstirred at reflux for 16 h. The mixture was allowed to cool to RT andquenched with saturated NaHCO₃ aqueous solution. The mixture wasextracted with ethyl acetate. The combined organic layer was washed withsaturated NaHCO₃ aqueous solution and brine, dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (ethyl acetate/petroleum ether=1:4) toyield the desired product (1.1 g, 94% yield) as a yellow solid.

7-Bromo-6-methoxyquinazolin-4(1H)-one

The product was made from methyl 2-amino-4-bromo-5-methoxybenzoate in 6steps followed the procedure described in Example 2. ESI-MS m/z: 393.8[M+H]⁺.

1-(4-(7-(2-Fluorophenyl)-6-hydroxyquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

BBr₃ (127 mg, 0.51 mmol) was added into a solution of1-(4-(7-(2-fluorophenyl)-6-methoxyquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one(20 mg, 0.051 mmol) in dichloromethane (5 mL) at −78° C. and stirred at40° C. for 1 h. Then it was cooled to −78° C., quenched with saturatedNaHCO₃ aqueous solution extracted with dichloromethane. The organiclayer was washed with saturated NaHCO₃ aqueous solution and brine, driedover Na₂SO₄ and concentrated in vacuo. The residue was purified byPrep-HPLC to yield the desired product (7 mg, 36% yield) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d6): δ 10.44 (bs, 1H), 8.57 (s, 1H), 7.69(s, 1H), 7.51-7.46 (m, 3H), 7.33-7.29 (m, 1H), 6.87 (dd, J=10.4, 16.4Hz, 1H), 6.18 (dd, J=2.0, 16.4 Hz, 1H) 5.75 (dd, J=2.4, 10.4 Hz, 1H),3.82-3.68 (m, 8H). ESI-MS m/z: 379.3 [M+H]⁺.

Example 29 Synthesis of1-(4-(6-chloro-7-(5-methyl-1H-indazol-4-yl)cinnolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 29 provides and exemplary preparation according to GeneralSynthetic Method N

5-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

To a solution of 5-methyl-1H-indazol-4-yl-4-boronic acid (300 mg, 1.7mmol) in THF (20 mL), pinacol (249 mg, 2.1 mmol) and MgSO₄ (614 mg, 5.1mmol) were added, and the resulting mixture was stirred at 45° C. for 3h. The mixture was filtered and rinsed with brine, dried over Na₂SO₄ andconcentrated in vacuo to afford the desired product (330 mg, 75% yield).

1-(2-Amino-4-bromo-5-chlorophenyl)ethanone

To a stirred solution of BCl₃ (51 mL, 51 mmol) in toluene at 0° C.,3-bromo-4-chlorobenzenamine (10 g, 48.4 mmol) in CH₃CN (90 mL) was addeddropwise over 20 min. To this suspension, AlCl₃ (7.1 g, 53.2 mmol) wasadded in three portions. The mixture was stirred at reflux for 16 h. Themixture was cooled to 0° C., HCl (4 N, 100 mL) was added and theresulting mixture was stirred at reflux for 2 h. The mixture was allowedto cool to RT and extracted with ethyl acetate. The organic layer waswashed with 2 N HCl and brine, dried over Na₂SO₄, and concentrated invacuo. The residue was purified by flash column chromatography on silicagel (petroleum ether/ethyl acetate=4:1) to afford the desired product(1.6 g, 11% yield).

7-Bromo-6-chlorocinnolin-4(1H)-one

To a mixture of concentrated HCl (20 mL) and1-(2-amino-4-bromo-5-chlorophenyl)ethanone (1.6 g, 6.44 mmol) at 0° C.,sodium nitrite (466 mg, 6.76 mmol) in water (1 mL) was slowly added(over 30 min). The mixture was stirred at 0° C. for 30 min and thenstirred at 60° C. for 2 h. The mixture was allowed to cool to RT andpoured into water. The solid was collected by filtration to afford thedesired product (1.4 g, 84% yield).

7-Bromo-4,6-dichlorocinnoline

Thionyl chloride (10 mL) and DMF (3 drops) was added to7-bromo-6-chlorocinnolin-4(1H)-one (1.4 g, 5.4 mmol), and the resultingmixture was stirred at reflux for 2 h. The mixture was concentrated invacuo to afford the crude product (1.5 g) which was used in next stepwithout further purification.

tert-Butyl 4-(7-bromo-6-chlorocinnolin-4-yl)piperazine-1-carboxylate

A mixture of 7-bromo-4,6-dichlorocinnoline (1.5 g, 5.4 mmol), tert-butylpiperazine-1-carboxylate (1.51 g, 8.1 mmol), DIEA (2.1 g, 16.2 mmol) and1,4-dioxane (20 mL) was stirred at reflux for 16 h. The mixture wasallowed to cool to RT, poured into ice water, and extracted with ethylacetate. The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated. The residue was purified by flash column chromatography onsilica gel (petroleum ether/ethyl acetate=1:1) to afford the desiredproduct (1.8 g, 78% yield). ESI-MS m/z: 429.05 [M+H]⁺.

tert-Butyl4-(6-chloro-7-(5-methyl-1H-indazol-4-yl)cinnolin-4-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(7-bromo-6-chlorocinnolin-4-yl)piperazine-1-carboxylate (138 mg, 0.32mmol) and5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole(250 mg, 0.97 mmol) in 1,4-dioxane (10 mL) and water (2 mL), Pd(PPh₃)₄(37 mg, 0.0325 mmol) and Na₂CO₃ (136 mg, 1.28 mmol) were added. Themixture was stirred at 100° C. for 16 h. The mixture was allowed to coolto RT and concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel (dichloromethane/methanol=20:1) toafford the desire product (140 mg, 91% yield).

1-(4-(6-Chloro-7-(5-methyl-1H-indazol-4-yl)cinnolin-4-yl)piperazin-1-yl)prop-2-en-1-one

The mixture of4-(6-chloro-7-(5-methyl-1H-indazol-4-yl)cinnolin-4-yl)piperazine-1-carboxylate(140 mg, 0.29 mmol) in HCl/MeOH (20 mL, 2.8 N) was stirred for 1 h. Themixture was concentrated in vacuo and the residue was dissolved in DCM(5 mL) and Et₃N (88 mg, 0.87 mmol). This mixture was cooled to −60° C.,acryloyl chloride (26 mg, 0.29 mmol) was added slowly. The reactionmixture was stirred at RT for 1 h. The mixture was partitioned betweenethyl acetate and water. The organic layer was washed with brine, driedover Na₂SO₄ and concentrated in vacuo. The residue was purified byPrep-HPLC to afford the desired product (12 mg, 10% yield) as a whitesolid. ¹H NMR (400 MHz, DMSO-d6) δ: 13.18 (s, 1H), 9.08 (s, 1H), 8.34(m, 2H), 7.57 (m, 2H), 7.39 (d, J=8.4 Hz, 1H), 6.90 (dd, J=10.8, 16.4Hz, 1H), 6.20 (d, J=16.4 Hz, 1H), 5.77 (d, J=10.4 Hz, 1H), 3.91-3.88 (m,4H), 3.51 (m, 4H), 2.20 (s, 3H). ESI-MS m/z: 433.1 [M+H]⁺.

Example 30 Synthesis of1-(4-(6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 30 provides an exemplary preparation according to GeneralSynthetic Method O

3-Bromo-2-fluorobenzenamine

To a mixture of 1-bromo-2-fluoro-3-nitrobenzene (13.75 g, 62.76 mmol),HOAc (26.36 g, 439 mmol), EtOH (150 mL) and H₂O (60 mL) at roomtemperature, iron powder (9.14 g, 163 mmol) was added portion-wise. Theresulting mixture was stirred at room temperature for 16 h and then wasneutralized with NaOH (5 N) solution. Then the mixture was extractedwith ethyl acetate. The organic layer was washed with brine, dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel (petroleum ether/ethyl acetate=10:1)to afford the desired product (7.77 g, 65% yield) as a brown oil.

N-(3-Bromo-2-fluorophenyl)-2-(hydroxyimino)acetamide

A mixture of 2,2,2-trichloroethane-1,1-diol (8.09 g, 49.33 mmol) andNa₂SO₄ (53 g, 370 mol) was dissolved in water and warmed to 35° C.3-Bromo-2-fluorobenzenamine (7.77 g, 41.11 mmol) in water was added,followed by 35% aqueous HCl solution (4.6 mL) and hydroxylaminehydrochloride (9.08 g, 131.6 mmol). The resulting mixture was stirred at90° C. for 16 h and yellow precipitate was formed. The mixture wascooled to room temperature. The solid was collected by filtration,rinsed with water, and dried in the air to afford the desired product(6.5 g, 61% yield).

6-Bromo-7-fluoroindoline-2,3-dione

To the concentrated sulfuric acid (20 mL),N-(3-bromo-2-fluorophenyl)-2-(hydroxyimino)acetamide (1.82 g, 7.03 mmol)was added at 60° C. The temperature was raised to 90° C. and maintainedfor 3 h. The reaction mixture was cooled to room temperature and pouredinto ice. The yellow precipitate was collected by filtration and driedto afford the desired product (1.41 g, 82% yield). ¹H NMR (400 MHz,DMSO-d6) δ: 11.75 (s, 1H), 7.39 (dd, J=5.7, 7.9 Hz, 1H), 7.31 (d, J=8.2Hz, 1H).

2-Amino-4-bromo-3-fluorobenzoic acid

To a solution of 6-bromo-7-fluoroindoline-2,3-dione (1.41 g, 5.80 mmol)in 2 N NaOH (15 mL), H₂O₂ solution (30%, 3 mL) was added at 0° C. andthe resulting mixture was stirred at 0° C. for 30 min. After stirring atroom temperature for 16 h, the mixture was poured into ice-water, andthe solution was acidified with conc. HCl solution. The precipitate wascollected by filtration and dried in the air to afford the desiredproduct (1.2 g, 89% yield) as a white solid.

2-Amino-4-bromo-5-chloro-3-fluorobenzoic acid

To a solution of 2-amino-4-bromo-3-fluorobenzoic acid (234 mg, 1.00mmol) in DMF (10 mL), NCS (134 mg, 1 mmol) was added at room temperatureand the resulting mixture was stirred at 70° C. for 16 h. The mixturewas poured into ice-water. The precipitate was collected by filtration,rinsed with water and dried to afford the desired product (209 mg, 78%yield) as a white solid. ESI-MS m/z: 269.8 [M+H]⁺.

7-Bromo-6-chloro-8-fluoroquinazolin-4(3H)-one

To a solution of 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (1.07 g,3.98 mmol) in EtOH (15 mL), formamidine acetate (4.92 g, 47.76 mmol) wasadded at room temperature and the resulting mixture was stirred atreflux for 16 h. The mixture was allowed to cool to room temperature andthen concentrated in vacuo. The residue was partitioned between ethylacetate and water. The organic layer was washed with brine, dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by columnchromatography on silica gel (dichloromethane/methanol=100:1 to 50:1) toafford the desired product (600 mg, 55% yield) as a white solid. ESI-MSm/z: 278.9 [M+H]⁺.

7-Bromo-4,6-dichloro-8-fluoroquinazoline

A mixture of 7-bromo-6-chloro-8-fluoroquinazolin-4(3H)-one (600 mg, 2.16mmol), SOCl₂ (30 mL) and DMF (3 drops) was stirred at reflux for 16 h.The mixture was allowed to cool to room temperature and thenconcentrated in vacuo to afford the crude product (639 mg), which wasused directly in the next step.

tert-Butyl4-(7-bromo-6-chloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate

To a solution of 7-bromo-4,6-dichloro-8-fluoroquinazoline (639 mg, 2.16mmol) in 1,4-dioxane (20 mL), tert-butyl piperazine-1-carboxylate (1.21g, 6.48 mmol) and DIPEA (1.39 g, 10.8 mmol) were added at roomtemperature. The resulting mixture was stirred at 50° C. for 3 h. Themixture was allowed to cool to room temperature and concentrated invacuo. The residue was partitioned between ethyl acetate and saturatedNaHCO₃ solution. The organic layer was washed with brine, dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by columnchromatography on silica gel (dichloromethane/methanol=100:1) to affordthe desired product (950 mg, 98% yield) as a yellow solid. ESI-MS m/z:446.1 [M+H]⁺.

tert-Butyl4-(6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate

A mixture of tert-butyl4-(7-bromo-6-chloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate (45mg, 0.1 mmol), 2-fluoro-6-methoxyphenylboronic acid (85 mg, 0.5 mmol),Pd(PPh₃)₄ (6 mg, 0.05 mmol) and Na₂CO₃ (53 mg, 0.5 mmol) in1,4-dioxane/H₂O (8 mL/2 mL) was stirred at 85° C. under an argonatmosphere for 16 h. The mixture was allowed to cool to room temperatureand concentrated in vacuo. The residue was purified by columnchromatography on silica gel (dichloromethane/methanol=100:1) to affordthe desired product (46 mg, 92% yield) as a yellow solid. ESI-MS m/z:491.2 [M+H]⁺.

1-(4-(6-Chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

A mixture oftert-butyl4-(6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazine-1-carboxylate(136 mg, 0.277 mmol) and HCl in MeOH (6 mL, 2.8 N) was stirred at roomtemperature for 1 h. The mixture was concentrated in vacuo to yield thecrude product (118 mg) as a yellow solid which was used directly in thenext step.

Acryloyl chloride (30 mg, 0.33 mmol) was added to the mixture of theabove obtained crude6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-(piperazin-1-yl)quinazoline(118 mg, 0.277 mmol) in Et₃N (140 mg, 1.38 mmol) and dichloromethane (15mL) at 0° C. The resulting mixture was stirred at 0° C. for 2 h. Themixture was quenched with saturated NaHCO₃ solution, and then extractedwith ethyl acetate. The organic layer was washed with saturated NaHCO₃solution and brine, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography on silica gel(dichloromethane/methanol=80:1) to yield the desired product (61 mg, 49%yield) as a solid.

1-(4-(6-Chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

To a solution of1-(4-(6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one(61 mg, 0.137 mmol) in dichloromethane (10 mL) at −78° C. under nitrogenatmosphere, BBr₃ (343 mg, 1.37 mmol) was added and the resulting mixturewas stirred at room temperature for 3 h. The mixture was quenched withsaturated NaHCO₃ solution at −30° C. and then extracted with ethylacetate. The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by pre-TLC to afford thedesired product (45 mg, 76% yield) as a solid. ¹H NMR (400 MHz, DMSO-d6)δ:10.30 (s, 1H), 8.70 (s, 1H), 8.04 (s, 1H), 7.34-7.40 (m, 1H),6.80-6.87 (m, 3H), 6.16-6.20 (m, 1H), 5.73-5.76 (m, 1H), 3.77-3.93 (m,8H). ESI-MS m/z: 431.1 [M+H]⁺.

Example 31 Synthesis of4-(4-acryloylpiperazin-1-yl)-6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinoline-3-carbonitrile

Example 31 provides an exemplary preparation according to GeneralSynthetic Method P

3-Bromo-4-chloro-2-fluorobenzenamine

To a solution of 3-bromo-2-fluorobenzenamine (1.9 g, 10 mmol) in DMF (10mL) at room temperature, NCS (1.4 g, 10.5 mmol) was added and theresulting mixture was stirred at room temperature for 16 h. The mixturewas poured into ice-water and extracted with ethyl acetate. The organiclayer was washed with brine, dried over Na₂SO₄ and concentrated invacuo. The residue was purified by flash column chromatography on silicagel (petroleum ether/ethyl acetate=30:1) to afford the desired product(1.15 g, 51% yield) as a solid. ESI-MS m/z: 225.9 [M+H]⁺.

Diethyl 2-((3-bromo-4-chloro-2-fluorophenylamino)methylene)malonate

A mixture of 3-bromo-4-chloro-2-fluorobenzenamine (2.3 g, 10.2 mmol) anddiethyl 2-(ethoxymethylene)malonate (2.42 g, 11.22 mmol) was stirred at120° C. for 3 h. The mixture was allowed to cool to room temperature,and then petroleum ether was added. The mixture was stirred at roomtemperature for 1 h. The precipitate was collected by filtration anddried to afford the desired product (2.76 g, 68.7% yield) as a solid.ESI-MS m/z: 395.9 [M+H]⁺.

Ethyl 7-bromo-6-chloro-8-fluoro-4-hydroxyquinoline-3-carboxylate

Diethyl 2-((3-bromo-4-chloro-2-fluorophenylamino)methylene)malonate(2.76 g, 6.99 mmol) was suspended in Ph₂O (20 mL). The mixture wasstirred at 250° C. for 2 h. The mixture was allowed to cool to roomtemperature and then 100 mL of petroleum ether was added. The whitesolid was collected by filtration and rinsed with petroleum ether (100mL) to afford the desired product (1.85 g, 76% yield) as a solid. ESI-MSm/z: 349.9 [M+H]⁺.

Ethyl 7-bromo-4,6-dichloro-8-fluoroquinoline-3-carboxylate

A mixture of ethyl7-bromo-6-chloro-8-fluoro-4-hydroxyquinoline-3-carboxylate (1.85 g, 5.31mmol) and POCl₃ (10 mL) was stirred at reflux for 4 h. The mixture wasallowed to cool to room temperature and concentrated in vacuo to affordthe crude product (1.41 g).

Ethyl4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-7-bromo-6-chloro-8-fluoroquinoline-3-carboxylate

A mixture of ethyl 7-bromo-4,6-dichloro-8-fluoroquinoline-3-carboxylate(1.41 g, 3.84 mmol), tert-butyl piperazine-1-carboxylate (1.43 g, 7.68mmol), Et₃N (1.55 g, 15.36 mmol) and DMSO (20 mL) was stirred at 80° C.under an argon atmosphere for 2 h. The mixture was allowed to cool toroom temperature and poured into ice-water. The mixture was extractedwith ethyl acetate. The combined organic layer was washed with brine,dried over Na₂SO₄, and concentrated in vacuo. The residue was purifiedby flash column chromatography on silica gel (petroleum ether/ethylacetate=3:1) to afford the desired product (1.96 g, 98% yield) as asolid. ESI-MS m/z: 518.1 [M+H]⁺.

4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-7-bromo-6-chloro-8-fluoroquinoline-3-carboxylicacid

To a solution ofethyl4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-7-bromo-6-chloro-8-fluoroquinoline-3-carboxylate(517 mg, 1 mmol) in EtOH/H₂O (16 mL/8 mL), LiOH.H₂O (126 mg, 3 mmol) wasadded. The mixture was stirred at room temperature for 16 h and pouredinto ice-water. The mixture was acidified with 1N HCl solution andextracted with ethyl acetate. The organic layer was washed with brine,dried over Na₂SO₄ and concentrated in vacuo to afford the desiredproduct (489 mg, 100% yield) as a solid. ESI-MS m/z: 489.1 [M+H]⁺.

tert-Butyl4-(7-bromo-3-carbamoyl-6-chloro-8-fluoroquinolin-4-yl)piperazine-1-carboxylate

A mixture of4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-7-bromo-6-chloro-8-fluoroquinoline-3-carboxylicacid (290 mg, 0.59 mmol), HOBt (121 mg, 0.89 mmol), NH₄Cl (63 mg, 1.18mmol), DIPEA (306 mg, 2.37 mmol) in DMF (16 ml) at room temperature, BOP(393 mg, 0.89 mmol) was added and the resulting mixture was stirred atroom temperature for 16 h. The mixture was poured into ice-water andextracted with ethyl acetate. The organic layer was washed with brine,dried over Na₂SO₄ and concentrated in vacuo. The residue was purified byflash column chromatography on silica gel(dichloromethane/methanol=15:1) to afford the desired product (160 mg,55% yield) as a white solid. ESI-MS m/z: 533.2 [M+H]⁺.

tert-Butyl-4-(3-carbamoyl-6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinolin-4-yl)piperazine-1-carboxylate

A mixture oftert-butyl-4-(7-bromo-3-carbamoyl-6-chloro-8-fluoroquinolin-4-yl)piperazine-1-carboxylate(100 mg, 0.21 mmol), 2-fluoro-6-methoxyphenylboronic acid (174 mg, 1.025mmol), Pd(PPh₃)₄ (12 mg, 0.01 mmol) and Na₂CO₃ (109 mg, 1.02 mmol) in1,4-dioxane/H₂O (12 mL/3 mL) was stirred at 100° C. under an argonatmosphere for 16 h. The mixture was allowed to cool to room temperatureand concentrated in vacuo. The residue was purified by pre-TLC to affordthe desired product (71 mg, 65% yield) as a white solid.

4-(4-Acryloylpiperazin-1-yl)-6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinoline-3-carboxamide

A mixture of tert-butyl4-(3-carbamoyl-6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinolin-4-yl)piperazine-1-carboxylate(71 mg, 0.13 mmol) and HCl in MeOH (8 mL, 2.8 N) was stirred at roomtemperature for 1 h. The mixture was concentrated in vacuo to afford thecrude6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)-4-(piperazin-1-yl)quinoline-3-carboxamidehydrochloride.

The above obtained crude compound was dissolved in Et₃N (40 mg, 0.40mmol) and dichloromethane (15 mL) and cooled to 0° C., acryloyl chloride(14 mg, 0.16 mmol) was added to the mixture. The resulting mixture wasstirred at 0° C. for 2 h. The reaction mixture was quenched withsaturated NaHCO₃ aqueous solution, and then extracted with ethylacetate. The organic layer was washed with saturated NaHCO₃ solution andbrine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by pre-TLC to afford the desired product (62 mg, 95% yield) asa white solid. ESI-MS m/z: 487.2 [M+H]⁺.

4-(4-Acryloylpiperazin-1-yl)-6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinoline-3-carboxamide

To a solution of4-(4-acryloylpiperazin-1-yl)-6-chloro-8-fluoro-7-(2-fluoro-6-methoxyphenyl)quinoline-3-carboxamide(62 mg, 0.13 mmol) in dichloromethane (10 mL) at −78° C. under nitrogenatmosphere, BBr₃ (317 mg, 1.27 mmol) was added and the resulting mixturewas stirred at room temperature for 3 h. The reaction mixture wasquenched with saturated NaHCO₃ at −30° C., and the aqueous solution wasextracted with ethyl acetate. The organic layer was washed with brine,dried over Na₂SO₄ and concentrated in vacuo to afford the desiredproduct as a yellow solid (60 mg, 100% yield).

4-(4-Acryloylpiperazin-1-yl)-6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinoline-3-carbonitrile

A mixture of4-(4-acryloylpiperazin-1-yl)-6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinoline-3-carboxamide,TEA (64 mg, 0.635 mmol) in dichloromethane (10 mL) at 0° C., TFAA (80mg, 0.38 mmol) was added. The mixture was stirred at 0° C. for 2 h andthen poured into saturated NaHCO₃ solution. The mixture was extractedwith ethyl acetate. The organic layer was washed with brine, dried overNa₂SO₄ and concentrated. The residue was purified by pre-TLC to affordthe desired product (15 mg, 26% yield) as a white solid. ¹H NMR (400MHz, DMSO-d6) δ: 10.33 (s, 1H), 8.89 (s, 1H), 8.08 (d, J=0.4, 1H),7.35-7.41 (m, 1H), 6.81-6.94 (m, 3H), 6.17-6.22 (m, 1H), 5.74-5.77 (m,1H), 3.85-3.89 (m, 4H), 3.73 (m, 4H). ESI-MS m/z: 455.2 [M+H]⁺.

Example 32 Synthesis of1-(4-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 32 provides an exemplary preparation according to GeneralSynthetic Method Q

1-(4-(7-Bromo-6-chloro-8-fluoroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

tert-Butyl4-(7-bromo-6-chloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate(300 mg, 0.67 mmol) was dissolved in TFA and DCM (50% TFA, 5 mL) and theresulting mixture was stirred at room temperature for 30 min. Themixture was concentrated in vacuo. The residue was dissolved in DCM andwashed with sat. NaH-CO₃ solution. The organic layer was dried overMgSO₄, filtered and concentrated in vacuo. The residue was dissolved inDCM at 0° C., iPr₂NEt (262 mg, 2 mml) was added, followed by acryloylchloride (122 mg, 1.35 mmol). The mixture was stirred at 0° C. for 30min. The mixture was concentrated in vacuo, and the residue was purifiedvia Isolera One (MeOH/DCM=0-3%) to afford the desired product (250 mg,93% yield).

1-(4-(6-Chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

A mixture of1-(4-(7-bromo-6-chloro-8-fluoroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one(30 mg, 0.075 mmol), (5-methyl-1H-indazol-4-yl)boronic acid (20 ng,0.113 mmol) and Tetrakis (43 mg, 0.038 mmol) in co-solvent of1,4-dioxane (3 mL) and 1 M Na₂CO₃ (0.5 rnL) was heated in microwavereactor at 120° C. for 15 main. The mixture was partitioned between DCMand water. The organic layer was dried over Na, SO₄ and concentrated invacuo. The residue was purified via Isolear One (MeOH/DCM=0-10%)followed by prep-TLC (MeOH/DCM=10%) to afford the desired product (9 mg,26.6% yield). H NMR (500 MHz, CDCl₃) δ: 8.86 (s, 1H), 9.08 (s, 1H), 7.90(s, 1H), 7.59 (s, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.40 (d, J=8.5 Hz, 1H),6.62 (dd, J=10.5, 17 Hz, 1H), 6.40 (dd, J=1.5, 17 Hz, 1H), 5.80 (dd,J=1.5, 10.5 Hz, 1H), 3.78-4.02 (m, 8H), 2.25 (s, 3H). ESI-MS m/z: 451.1[M+H]⁺.

Example 33 Synthesis of1-(4-(7-(2-fluorophenyl)-6-(trifluoromethyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 33 provides an exemplary preparation according to GeneralSynthetic Method R

Methyl 2-amino-4-chloro-5-iodobenzoate

To a mixture of I₂ (6.8 g, 27.0 mmol) and Ag₂SO₄ (8.4 g, 27.0 mmol) inEtOH (250 mL), methyl 2-amino-4-chlorobenzoate (5.0 g, 27.0 mmol) wasadded and the resulting mixture was stirred at RT for 45 min. The solidwas filtered off and washed with dichloromethane, and the filtrate wasconcentrated in vacuo. The residue was extracted with dichloromethaneand washed with brine. The organic layer was dried over Na₂SO₄ andconcentrated in vacuo to afford the desired product (6.4 g, 76% yield)as a white solid. ESI-MS m/z: 311.9 [M+H]⁺.

Methyl 2-acetamido-4-chloro-5-iodobenzoate

A mixture of methyl 2-amino-4-chloro-5-iodobenzoate (8.4 g, 0.027 mol),pyridine (6.4 g, 0.081 mol) in dichloromethane (250 mL) at 0° C., acetylchloride (2.5 g, 0.032 mol) was added. The mixture was stirred at RT for16 h. The reaction mixture was washed with brine. The organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by flash column chromatography on silica gel (ethylacetate/petroleum ether=1:5) to afford the desired product (7.6 g, 80%yield). ESI-MS m/z: 353.9 [M+H]⁺.

Methyl 2-amino-4-chloro-5-(trifluoromethyl)benzoate

To a stirred solution of methyl 2-acetamido-4-chloro-5-iodobenzoate (2.5g, 7.08 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.72 g,14.2 mmol) in NMP (30 mL) at RT, CuI (0.4 g, 2.12 mmol) was added andthe resulting mixture was stirred at 80° C. for 16 h. The mixture wasquenched with water and partitioned between water and ethyl acetate. Theorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo. The residue was purified by flash column chromatography onsilica gel (ethyl acetate/petroleum ether=1:5) to afford the desiredproduct (1.8 g, 90% yield) as a light yellow oil. ESI-MS m/z: 296.4[M+H]⁺.

Methyl 2-amino-4-chloro-5-(trifluoromethyl)benzoate

A mixture of methyl 2-amino-4-chloro-5-(trifluoromethyl)benzoate (800mg, 2.71 mmol) in HCl/MeOH (2.85 mol/L, 10 mL) was stirred at 80° C. for1.5 h. The reaction mixture was concentrated in vacuo to afford thedesired product which was used in the next step without furtherpurification.

2-Amino-4-chloro-5-(trifluoromethyl)benzoic acid

To a mixture of methyl 2-amino-4-chloro-5-(trifluoromethyl)benzoate (600mg, 2.55 mmol) in THF (10 mL) and water (2.5 mL) at RT, LiOH.H₂O (408mg, 10.21 mmol) was added and the resulting mixture was stirred at 80°C. for 3 h. The mixture was diluted with H₂O, acidified with HCl toadjust pH to 4 and then extracted with ethyl acetate. The organic layerwas washed with brine, dried over Na₂SO₄ and concentrated in vacuo toafford the desired product (500 mg, 82% yield) as a solid.

7-Chloro-6-(trifluoromethyl)quinazolin-4-ol

A mixture of 2-amino-4-chloro-5-(trifluoromethyl)benzoic acid (500 mg,2.09 mmol) and formamidine acetate (430 mg, 4.18 mmol) in2-ethoxyethanol (15 mL) was stirred at reflux for 16 h. The mixture wasconcentrated in vacuo and extracted with dichloromethane. The organiclayer was washed with brine, dried over Na₂SO₄ and concentrated toafford the desired product (500 mg, 96% yield) which was used in thenext step without further purifications. ESI-MS m/z: 249.3 [M+H]⁺.

4,7-Dichloro-6-(trifluoromethyl)quinazoline

To a suspension of 7-chloro-6-(trifluoromethyl)quinazolin-4-ol (500 mg,0.016 mol) in SOCl₂ (20 mL), DMF (one drop) was added and the resultingmixture was stirred at reflux for 3 h. The mixture was concentrated invacuo to afford the crude product which was used in the next stepwithout further purification

tert-Butyl4-(7-chloro-6-(trifluoromethyl)quinazolin-4-yl)piperazine-1-carboxylate

To a solution of 4,7-dichloro-6-(trifluoromethyl)quinazoline (500 mg,1.88 mmol) and Et₃N (3.33 g, 33 mmol) in dichloromethane (20 mL) at RT,tert-butyl piperazine-1-carboxylate (3.07 g, 16.5 mmol) was added. Theresulting mixture was stirred at RT for 16 h. The mixture was washedwith saturated NH₄Cl solution and brine, dried over Na₂SO₄ andconcentrated. The residue was purified by flash column chromatography onsilica gel (50% ethyl acetate/petroleum ether) to afford the desiredproduct (650 mg, 83% yield) as a yellow solid. ESI-MS m/z: 417.0 [M+H]⁺.

tert-Butyl4-(6-(trifluoromethyl)-7-(2-fluorophenyl)quinazolin-4-yl)piperazine-1-carboxylate

The mixture of4-(7-chloro-6-(trifluoromethyl)quinazolin-4-yl)piperazine-1-carboxylate(200 mg, 0.48 mmol), 2-fluorophenylboronic acid (132.6 mg, 0.96 mmol),PdCl₂(dppf) (35 mg, 0.048 mmol), Na₂CO₃ (254 mg, 2.4 mmol) in dioxane(20 mL) and water (2 mL) was stirred at 100° C. under argon for 16 h.The mixture was allowed to cool to RT and concentrated in vacuo. Theresidue was purified by flash column chromatography on silica gel (50%ethyl acetate/petroleum ether) to afford the desired product (100 mg,44% yield) as a white solid.

1-(4-(6-(Trifluoromethyl)-7-(2-fluorophenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

The title compound was prepared from tert-butyl4-(6-(trifluoromethyl)-7-(2-fluorophenyl)quinazolin-4-yl)piperazine-1-carboxylateaccording to the procedure described in steps 5 and 6 in Example 1. ¹HNMR (400 MHz, DMSO-d6) δ: 9.74 (s, 1H), 8.43 (s, 1H), 7.78 (s, 1H),7.58-7.53 (m, 1H), 7.44-7.32 (m, 3H), 6.87-6.80 (dd, J=11.0, 16.4 Hz,1H), 6.21 (dd, J=2.4, 16.8 Hz, 1H), 5.77 (dd, J=2.1, 10.0 Hz, 1H),4.06-4.00 (m, 4H), 3.05-3.77 (m, 4H). ESI-MS m/z: 431.2 [M+H]⁺.

Example 34 Synthesis of1-(1-acryloylpiperidin-4-yl)-7-chloro-6-(2,4-difluorophenyl)quinoxalin-2(1H)-one

Example 34 provides an exemplary preparation according to GeneralSynthetic Method S

tert-Butyl 4-(2-chloroacetamido)piperidine-1-carboxylate

To a mixture of tert-butyl 4-aminopiperidine-1-carboxylate (5 g, 25mmol), Et₃N (4.5 mL, 32.3 mmol) in dichloromethane (50 mL) at 0° C.,2-chloroacetyl chloride (3.4 g, 30 mmol) was added dropwise. Thereaction mixture was allowed to warm to RT and stirring was continueduntil conversion was completed. The reaction mixture was washed withNaHCO₃ aqueous solution and brine. The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (20-50% ethylacetate/petroleum ether) to afford the desired product (4 g, 57.8%yield).

5-Bromo-4-chloro-2-iodobenzenamine

A mixture of 3-bromo-4-chlorobenzenamine (15 g, 72.6 mmol) in HOAc (100mL), NIS (19.6 g, 87.1 mmol) was added and the resulting mixture wasstirred at RT for 6 h. The mixture was quenched with water, andextracted with ethyl acetate. The organic layer washed with brine, driedover Na₂SO₄ and concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel (5% petroleum ether/ethyl acetate)to afford the desired product (5.2 g, 21.6% yield).

N-(5-Bromo-4-chloro-2-iodophenyl)methanesulfonamide

A mixture of 5-bromo-4-chloro-2-iodobenzenamine (5.2 g, 15.6 mmol), Et₃N(4.7 g, 46.8 mmol) in dichloromethane (60 mL) at 0° C., methanesulfonylchloride (2.2 g, 18.8 mmol) was added dropwise. The resulting mixturewas stirred at RT for 10 h. The mixture was quenched with water, andextracted with dichloromethane. The organic layer was washed with brine,dried over Na₂SO₄ and concentrated in vacuo. The residue was purified byflash column chromatography on silica gel (10% petroleum ether/ethylacetate) to afford the desired product (5 g, 78.1% yield).

tert-Butyl4-(2-(N-(5-bromo-4-chloro-2-iodophenyl)methylsulfonamido)acetamido)piperidine-1-carboxylate

A mixture of 5-bromo-4-chloro-2-iodo-N-methanesulfonybenzenamine (1.6 g,3.9 mmol), tert-butyl 4-(2-chloroacetamido)piperidine-1-carboxylate(1.08 g, 3.9 mmol), CuI (74 mg, 0.39 mmol), 1,10-phenanthroline (141 mg,0.78 mmol), K₂CO₃ (1.1 g, 7.58 mmol) in dioxane (20 mL) was stirred atreflux under argon for 12 h. The mixture was allowed to cool to RT,quenched with water, and then extracted with ethyl acetate. The organiclayer was washed with brine, dried over Na₂SO₄ and concentrated invacuo. The residue was purified by flash column chromatography on silicagel (30% petroleum ether/ethyl acetate) to afford the desired product(1.5 g, 59% yield).

tert-Butyl4-(6-bromo-7-chloro-2-oxoquinoxalin-1(2H)-yl)piperidine-1-carboxylate

A mixture of tert-butyl4-(2-(N-(5-bromo-4-chloro-2-iodophenyl)methylsulfonamido)acetamido)piperidine-1-carboxylate(1.5 g, 2.31 mmol), CuI (44 mg, 0.231 mmol), 1,10-phenanthroline (83 mg,0.462 mmol), Cs₂CO₃ (1.9 g, 5.78 mmol) in dioxane (10 mL) was stirred atreflux under argon for 12 h. The mixture was allowed to cool to RT,quenched with water, and extracted with ethyl acetate. The organic layerwas washed with brine, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography on silica gel (30%petroleum ether/ethyl acetate) to afford the desired product (55 mg,5.4% yield).

1-(1-Acryloylpiperidin-4-yl)-7-chloro-6-(2,4-difluorophenyl)quinoxalin-2(1H)-one

The title compound was prepared fromtert-butyl4-(6-bromo-7-chloro-2-oxoquinoxalin-1(2H)-yl)piperidine-1-carboxylate in three steps following the proceduredescribed in Example 2. ¹H NMR (400 MHz, DMSO-d6) δ: 8.24 (s, 1H), 7.86(s, 1H), 7.66 (s, 1H), 7.37-7.31 (m, 1H), 7.05-6.95 (m, 2H), 6.71-6.64(m, 1H), 6.38 (dd, J=2, 16.8 Hz, 1H), 5.74 (dd, J=2.0, 10.8 Hz, 1H),4.97 (m, 1H), 4.27 (m, 1H), 3.28 (m, 1H), 2.84 (m, 3H), 1.89 (m, 2H),1.66 (m, 1H) ESI-MS m/z: 430.3 [M+1]⁺.

Example 35 Synthesis of1-(4-(4-acryloylpiperazin-1-yl)-6-chloroquinazolin-7-yl)-5-chloropyridin-2(1H)-one

Example 35 provides an exemplary preparation according to GeneralSynthetic Method T

6-Fluoroquinazolin-4(1H)-one

A mixture of 2-amino-5-fluorobenzoic acid (8.0 g, 51.6 mmol) andformamidine acetate (10.6 g, 103 mmol) in EtOH (150 mL) was stirred atreflux for 16 h. The mixture was concentrated in vacuo and extractedwith dichloromethane. The organic layer was washed with brine, driedover Na₂SO₄ and concentrated in vacuo to afford the desired product (7.8g, 92% yield) which was used in the next step without furtherpurification.

6-Fluoro-7-nitroquinazolin-4(1H)-one

6-Fluoroquinazolin-4(1H)-one (4.3 g, 26.2 mmol) was added to a mixtureof concentrated H₂SO₄ (10 mL) and fuming HNO₃ (5 mL) at 0° C. Theresulting mixture was stirred at RT for 1 h and then stirred at 110° C.for 2 h. The mixture was cooled to RT and poured into ice-water. Theprecipitate was collected by filtration and dried to afford the desiredproduct (2.3 g, 42.6% yield) as a yellow solid. ESI-MS m/z: 210.3[M+H]⁺.

4-Chloro-7-fluoro-6-nitroquinazoline

A suspension of 6-fluoro-7-nitroquinazolin-4(1H)-one (2.3 g, 0.011 mol)in SOCl₂ (10 mL) was stirred at reflux for 3 h. The mixture was allowedto cool to RT, and concentrated in vacuo to afford the crude product(2.5 g) which was used in the next step without further purification.

tert-Butyl 4-(7-fluoro-6-nitroquinazolin-4-yl)piperazine-1-carboxylate

To a solution of 4-chloro-7-fluoro-6-nitroquinazoline (2.5 g, 11.0 mmol)in dichloromethane (50 mL) and Et₃N (3.33 g, 33 mmol) at RT, tert-butylpiperazine-1-carboxylate (3.07 g, 16.5 mmol) was added, and theresulting mixture was stirred at RT for 16 h. The mixture was washedwith saturated NH₄Cl solution and brine, dried over Na₂SO₄ andconcentrated. The residue was purified by flash column chromatography onsilica gel (50% ethyl acetate/petroleum ether) to afford the desiredproduct (1.8 g, 44% yield) as a yellow solid. ESI-MS m/z: 378.0 [M+H]⁺.

tert-Butyl4-(7-(5-chloro-2-oxopyridin-1(2H)-yl)-6-nitroquinazolin-4-yl)piperazine-1-carboxylate

To a solution of 5-chloropyridin-2-ol (213 mg, 1.39 mmol) in DMF (5 mL)at RT, NaH (55.6 mg, 1.39 mmol) was added and the resulting mixture wasstirred for 30 min. To this mixture, tert-butyl4-(7-fluoro-6-nitroquinazolin-4-yl)piperazine-1-carboxylate (350 mg,0.928 mmol) was added and the resulting mixture was stirred at 50° C.for 1.5 h. The mixture was allowed to cool to RT and partitioned betweenwater and ethyl acetate. The organic layer was washed with brine, driedover Na₂SO₄ and concentrated. The residue was purified by flash columnchromatography on silica gel (5% ethyl acetate/petroleum ether) toafford the desired product (400 mg, 88% yield) as a yellow solid. ESI-MSm/z: 487.2 [M+H]⁺.

tert-Butyl4-(6-amino-7-(5-chloro-2-oxopyridin-1(2H)-yl)quinazolin-4-yl)piperazine-1-carboxylate

A mixture of4-(7-(5-chloro-2-oxopyridin-1(2H)-yl)-6-nitroquinazolin-4-yl)piperazine-1-carboxylate(400 mg, 0.818 mmol), ammonium chloride (520 mg, 9.82 mmol), Zn powder(265.8 mg, 4.09 mmol) in EtOH (20 mL) and water (4 mL) was stirred at70° C. for 2 h. The mixture was concentrated in vacuo and extracted withdichloromethane. The organic layer was washed with NaHCO₃ and brine,dried over Na₂SO₄ and concentrated in vacuo. The residue was purified byflash column chromatography on silica gel (30% ethyl acetate/petroleumether) to afford the desired product (300 mg, 80.4% yield) as a solid.ESI-MS m/z: 457.2 [M+H]⁺.

tert-Butyl 4-(6-chloro-7-(5-chloro-2-oxopyridin-1(2H)-yl)quinazolin-4-yl)piperazine-1-carboxylate

To a mixture of tert-Butyl nitrite (135.5 mg, 1.32 mmol) and cupricchloride (280 mg, 1.65 mmol) in CH₃CN (10 mL), tert-butyl4-(6-amino-7-(5-chloro-2-oxopyridin-1(2H)-yl)quinazolin-4-yl)piperazine-1-carboxylate(300 mg, 0.658 mmol) in CH₃CN (5 mL) was added and the resulting mixturewas stirred at RT for 2 h. The mixture was partitioned between water andethyl acetate. The organic layer was washed with brine, dried overNa₂SO₄ and concentrated. The residue was purified by flash columnchromatography on silica gel (50% ethyl acetate/petroleum ether) toafford the desired product (110 mg, 38% yield).

1-(4-(4-Acryloylpiperazin-1-yl)-6-chloroquinazolin-7-yl)-5-chloropyridin-2(1H)-one

The title compound was prepared from tert-butyl4-(6-chloro-7-(5-chloro-2-oxopyridin-1(2H)-yl)quinazolin-4-yl)piperazine-1-carboxylate according to theprocedure described in steps 5 and 6 in Example 1. ¹HNMR (400 MHz,DMSO-d6) δ: 8.71 (s, 1H), 8.29 (s, 1H), 8.10 (s, 1H), 7.95 (d, 1H), 7.75(d, 1H), 6.87-6.80 (dd, J=12.0, 12.0 Hz, 1H), 6.46 (dd, J=8.0, 1H), 6.20(d, J=2.6, 16.8 Hz, 1H), 5.76 (dd, J=2.2, 10.0 Hz, 1H), 3.91-3.77 (m,8H). ESI-MS m/z: 430.4 [M+H]⁺.

Example 36 Synthesis of1-(4-(6-chloro-7-(2-(thiazol-2-yl)phenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 36 provides an exemplary preparation according to GeneralSynthetic Method U

tert-Butyl4-(7-(tributylstannyl)-6-chloroquinazolin-4-yl)piperazine-1-carboxylate

A mixture of tert-butyl4-(7-bromo-6-chloroquinazolin-4-yl)piperazine-1-carboxylate (1.5 g, 3.51mmol), 1,1,1,2,2,2-hexabutyldistannane (2.6 g, 4.56 mmol), Pd(PPh₃)₄(203 mg, 0.18 mmol) in toluene (40 mL) was stirred at reflux under argonfor 16 h. The mixture was allowed to cool to RT, quenched with water,and extracted with ethyl acetate. The organic layer was washed withbrine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (40% petroleumether/ethyl acetate) to afford the desired product (542 mg, 24% yield).

tert-Butyl4-(6-chloro-7-(2-(thiazol-2-yl)phenyl)quinazolin-4-yl)piperazine-1-carboxylate

A mixture oftert-butyl4-(7-(tributylstannyl)-6-chloroquinazolin-4-yl)piperazine-1-carboxylate(150 mg, 0.24 mmol), 2-(2-bromophenyl)thiazole (68 mg, 0.28 mmol),Pd(PPh₃)₄ (28 mg, 0.024 mmol), CsF (73 mg, 0.48 mmol) and CuI (9 mg,0.048 mmol) in DMF (10 mL) was stirred at 80° C. under argon for 16 h.Then reaction mixture was allowed to cool to room temperature, quenchedwith water, extracted with ethyl acetate. The organic layer was washedwith brine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel(dichloromethane/methanol=25:1) to afford the desired product (38 mg,31.1% yield).

1-(4-(6-Chloro-7-(2-(thiazol-2-yl)phenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

A mixture of4-(6-chloro-7-(2-(thiazol-2-yl)phenyl)quinazolin-4-yl)piperazine-1-carboxylate(38 mg, 0.075 mmol) in HCl/MeOH (2.86 M, 5 mL) was stirred at RT for 1h. The mixture was concentrated in vacuo to afford the crude product.The crude product was dissolved in dichloromethane (5 mL) at RT,acryloyl chloride (8 mg, 0.090 mmol) and Et₃N (23 mg, 0.225 mmol) wereadded and the resulting mixture was stirred at RT for 1 h. The mixturewas partitioned between dichloromethane and water. The organic layer waswashed brine, dried over MgSO₄, filtered and concentrated in vacuo. Theresidue was purified by flash column chromatography on silica gel(dichloromethane/methanol=20:1) to afford the desired product (8 mg, 23%yield, 2 steps). ¹H NMR (400 MHz, DMSO-d6) δ: 8.69 (s, 1H), 8.15 (d,J=2.4 Hz, 1H), 8.13 (s, 1H), 7.82 (s, 1H), 7.76 (d, J=3.2 Hz, 1H),7.67-7.60 (m, 3H), 7.43-7.41 (m, 1H), 6.87-6.81 (m, 1H), 6.18 (dd,J=2.0, 16.8 Hz, 1H), 5.75 (dd, J=2.0, 10.0 Hz, 1H), 3.92-3.78 (m, 8H).ESI-MS m/z: 462.3 [M+1]⁺.

Example 37 Synthesis of1-(4-(6,8-dichloro-7-(2-(fluorophenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 37 provides an exemplary preparation according to GeneralSynthetic Method V

2-Bromo-6-nitroaniline

A mixture of 1-bromo-2-fluoro-3-nitrobenzene (6.0 g, 27.27 mmol) and NH₃in CH₃OH (7 M, 20 mL) was stirred in a sealed tube at 100° C. for 16 h.The solvent was removed and the residue was dissolved in H₂O, and thenextracted with ethyl acetate. The organic layer was washed with brine,dried over Na₂SO₄ and concentrated. The residue was purified by columnchromatography on silica gel (ethyl acetate/petroleum ether=1:100) toafford the product as a yellow solid (5.4 g, 91.3% yield).

1-Bromo-2-chloro-3-nitrobenzene

A mixture of 2-bromo-6-nitroaniline (3.0 g, 13.84 mmol), tert-butylnitrite (2.85 g 27.68 mmol) and CuCl₂ (3.7 g, 27.68 mmol) in CH₃CN (60mL) was stirred at 60° C. under argon for 1 h. The mixture was allowedto cool to RT, quenched with H₂O, and extracted with ethyl acetate. Theorganic layer was washed with brine, dried over Na₂SO₄ and concentrated.The residue was purified by column chromatography on silica gel (ethylacetate/petroleum ether=1:100) to yield the product as an off-whitesolid (2.7 g, 82.7% yield).

3-Bromo-2-chloroaniline

A mixture of 1-bromo-2-chloro-3-nitrobenzene (2.7 g, 11.44 mmol) andSnCl₂ (12.97 g, 57.20 mmol) in CH₃CH₂OH (60 mL) was stirred at refluxfor 3 h. The mixture was allowed to cool to RT, quenched with H₂O, andextracted with ethyl acetate. The organic layer was washed with brine,dried over Na₂SO₄ and concentrated. The residue was purified by columnchromatography on silica gel (ethyl acetate/petroleum ether=1:50) toyield the product as an off-white solid (1.3 g, 55.2% yield).

1-(4-(6,8-Dichloro-7-(2-fluorophenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

The title compound was prepared from 3-bromo-2-chloroaniline accordingto the procedure described in Example 30. ¹H NMR (400 MHz, DMSO-d6) δ:8.76 (s, 1H), 8.20 (s, 1H), 7.61-7.57 (m, 1H), 7.45-7.40 (m, 3H), 6.83(dd, J=10.4, 16.8, 1H), 6.18 (dd, J=2.4, 16.8, 1H), 5.75 (dd, J=2.4,10.4, 1H), 3.93-3.76 (m, 8H). ESI-MS m/z: 430.1 [M+H]⁺.

Example 38 Synthesis of1-(4-(8-fluoro-7-(2-fluorophenyl)-6-(trifluoromethyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 38 provides an exemplary preparation according to GeneralSynthetic Method W

2-Amino-4-chloro-3-fluorobenzoic acid

The title compound was prepared from 3-chloro-2-fluorobenzenamineaccording to the procedure described in Example 30.

Methyl 2-amino-4-chloro-3-fluorobenzoate

To a solution of 2-amino-4-chloro-3-fluorobenzoic acid (7.0 g, 35.0mmol) in MeOH (100 mL) at 0° C., thionyl chloride (8.37 g, 70 mmol) wasadded dropwise. The mixture was warmed stirred at RT for 30 min, andthen stirred at reflux for 16 h. The mixture was concentrated in vacuo.The residue was extracted with dichloromethane and washed with brine.The organic layer was dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by flash column chromatography on silica gel (10%ethyl acetate/petroleum ether) to afford the desired product (4.0 g, 56%yield) as a white solid.

1-(4-(8-Fluoro-6-(trifluoromethyl)-7-(2-fluorophenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

The title compound was prepared from methyl2-amino-4-chloro-3-fluorobenzoate according to the procedure describedin Example 32. ¹HNMR (400 MHz, DMSO-d6) δ: 8.78 (s, 1H), 8.32 (s, 1H),7.61 (m, 1H), 7.49-7.37 (m, 3H), 6.87-6.80 (dd, J=11.0, 16.4 Hz, 1H),6.21-6.16 (dd, J=2.4, 16.8 Hz, 1H), 5.775.73 (dd, J=2.1, 10.0 Hz, 1H),4.06-4.00 (m, 4H), 3.85-3.72 (m, 4H). ESI-MS m/z: 449.2 [M+H]⁺

Example 39 Synthesis of1-(4-(7-(2-fluoro-6-hydroxyphenyl)-6-(trifluoromethyl)cinnolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 39 provides an exemplary preparation according to GeneralSynthetic Method X

1-(4-Chloro-2-nitrophenyl)ethanone

To a stirred solution of 4-chloro-2-nitrobenzoic acid (15.0 g, 75 mmol)in THF (250 mL) at 0° C., oxalyl chloride (13 mL, 150 mmol) was addedfollowed by DMF (2 drops). The mixture was stirred at 0° C. for 10 minand then stirred at reflux 2 h. The mixture was concentrated in vacuo todryness to afford 4-chloro-2-nitrobenzoyl chloride. To a solution ofdiethyl malonate (12.0 g, 75 mmol) in THF (250 mL), NaH (3.6 g, 90 mmol)was added in portions and the resulting mixture was stirred at RT for 20min. A solution of 4-chloro-2-nitrobenzoyl chloride in THF (100 mL) wasadded dropwise to the reaction mixture at 0° C. The resulting mixturewas stirred at RT for 30 min and then stirred at 80° C. for 2 h. Themixture was quenched with water and partitioned between water and ethylacetate. The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The residue was dissolved in AcOH (25 mL) and 20%H₂SO₄ (25 mL) and the resulting mixture was stirred at 80° C. for 6 h.The mixture was extracted with ethyl acetate, washed with brine, waterand NaHCO₃ solution. The organic layer was dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (ethyl acetate/petroleum ether=1:5) toafford the desired product (5.0 g, 33% yield) as a light yellow solid.

1-(2-Amino-4-chlorophenyl)ethanone

A mixture of methyl 1-(4-chloro-2-nitrophenyl)ethanone (5.0 g, 25 mmol)and Fe (5.6 g, 100 mmol) in CH₃COOH (50 mL) and H₂O (50 mL) was stirredat reflux for 16 h. The mixture was allowed to cool to RT and quenchedwith saturated NaHCO₃ aqueous solution. The mixture was extracted withethyl acetate. The organic layer was washed with saturated NaHCO₃aqueous solution and brine, dried over Na₂SO₄ and concentrated in vacuo.The residue was purified by flash column chromatography on silica gel(ethyl acetate/petroleum ether=1:4) to afford the desired product (3.8g, 89% yield) as a yellow solid.

1-(2-Amino-4-chloro-5-iodophenyl)ethanone

To a mixture of I₂ (4.5 g, 17.7 mmol) and Ag₂SO₄ (5.5 g, 17.7 mmol) inEtOH (100 mL), 1-(2-amino-4-chlorophenyl)ethanone (3.0 g, 17.7 mmol) wasadded and the resulting mixture was stirred at RT for 45 min. The solidwas filtered off and washed with dichloromethane, and the filtrate wasconcentrated in vacuo. The residue was extracted with dichloromethane.The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to afford the desired product (2.0 g, 38% yield)as a white solid. ESI-MS m/z: 295.3 [M+H]⁺.

N-(2-Acetyl-5-chloro-4-iodophenyl)acetamide

To a stirred solution of methyl 2-amino-4-chloro-3-fluoro-5-iodobenzoate(2.0 g, 6.8 mmol) and pyridine (1.6 g, 20.3 mmol) in DCM (50 mL) at 0°C., acetyl chloride (634 mg, 8.14 mmol) was added. The mixture wasstirred at RT for 16 h. The reaction mixture was washed with brine. Theorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo. The residue was purified by flash column chromatography onsilica gel (ethyl acetate/petroleum ether=1:5) to afford the desiredproduct (1.4 g, 61% yield). ESI-MS m/z: 338.4 [M+H]⁺.

N-(2-Acetyl-5-chloro-4-(trifluoromethyl)phenyl)acetamide

To a stirred solution of N-(2-acetyl-5-chloro-4-iodophenyl)acetamide(1.4 g, 4.2 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.6g, 8.3 mmol) in NMP (20 mL) at RT, CuI (235 mg, 1.24 mmol) was added andthe resulting mixture was stirred at 90° C. for 16 h. The mixture wasquenched with water and partitioned between water and ethyl acetate. Theorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedin vacuo. The residue was purified by flash column chromatography onsilica gel (ethyl acetate/petroleum ether=1:5) to afford the desiredproduct (1.0 g, 87% yield) as oil. ESI-MS m/z: 280.1 [M+H]⁺.

1-(2-Amino-4-chloro-5-(trifluoromethyl)phenyl)ethanone

The mixture of 2-acetamido-4-chloro-3-fluoro-5-(trifluoromethyl)benzoicacid (1.0 g, 3.58 mmol) in HCl/MeOH (2.85 M, 10 mL) was stirred at 60°C. for 1.5 h. The reaction mixture was concentrated in vacuo to affordthe desired product (900 mg) which was used in the next step withoutfurther purification.

7-Chloro-6-(trifluoromethyl)cinnolin-4(1H)-one

Concentrated HCl (10 mL) was added to1-(2-amino-4-chloro-5-(trifluoromethyl)phenyl)ethanone (900 mg, 3.58mmol). After the mixture was cooled to 0° C., a solution of sodiumnitrite (259 mg, 3.76 mmol) in water (2 mL) was added over 30 min. Themixture was stirred at 0° C. for 30 min and then stirred at 60° C. for 2h. The mixture was cooled and poured into water. The solid was collectedby filtration afford the desired the crude product (680 mg, 77% yield).

1-(4-(7-(2-Fluoro-6-hydroxyphenyl)-6-(trifluoromethyl)cinnolin-4-yl)piperazin-1-yl)prop-2-en-1-one

The title compound was prepared from7-chloro-6-(trifluoromethyl)cinnolin-4(1H)-one according to theprocedure described in Example 29. ¹HNMR (400 MHz, CDCl₃) δ: 9.06 (s,1H), 8.47 (s, 1H), 8.45 (s, 1H), 6.84 (m, 1H), 6.69-6.62 (dd, J=14.0,12.0 Hz, 1H), 6.44 (dd, J=2.6, 14.5 Hz, 1H), 5.85 (dd, J=2.2, 10.0 Hz,1H), 5.38 (m, 1H), 4.05-3.96 (m, 4H), 3.54-3.52 (m, 4H). ESI-MS m/z:447.2 [M+H]⁺.

Example 40 Synthesis of1-(4-(7-(2,4-difluorophenyl)-8-fluoro-6-methylquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 40 provides an exemplary preparation according to GeneralSynthetic Method AJ

3-Amino-2,2′,4′-trifluoro-[1,1′-biphenyl]-4-carboxylic acid

A mixture of 2-amino-4-bromo-3-fluorobenzoic acid (400 mg, 1.71 mmol),(2,4-difluorophenyl)boronic acid (405 mg, 1.5 mmol), Pd(PPh₃)₄ (197 mg,0.171 mmol) and Na₂CO₃ (725 mg, 6.84 mmol) in 1,4-dioxane/H₂O (10 mL/2mL) was stirred at 100° C. under argon for 16 h. The mixture was allowedto cool to RT and concentrated in vacuo. The residue was purified byflash column chromatography on silica gel(dichloromethane/methanol=20:1) to yield the desired product (374 mg,81.9% yield) as an off-white solid. ESI-MS m/z: 268.1 [M+H]⁺.

3-Amino-6-bromo-2,2′,4′-trifluoro-[1,1′-biphenyl]-4-carboxylic acid

A mixture of 3-amino-2,2′,4′-trifluoro-[1,1′-biphenyl]-4-carboxylic acid(374 mg, 1.4 mmol) and NBS (249 mg, 1.4 mmol) in DMF (4 mL) was stirredat RT for 2 h. The reaction mixture was quenched with H₂O, and thenextracted with ethyl acetate. The organic layer was washed with brine,dried over Na₂SO₄ and concentrated in vacuo. The residue was purified byflash column chromatography on silica gel (Petroleum ether/ethylacetate=2:1) to yield the desired product (330 mg, 67.9% yield) as agray solid. ESI-MS m/z: 345.9 [M+H]⁺.

6-Bromo-7-(2,4-difluorophenyl)-8-fluoroquinazolin-4-ol

A mixture of3-amino-6-bromo-2,2′,4′-trifluoro-[1,1′-biphenyl]-4-carboxylic acid (330mg, 0.95 mmol) and formimidamide acetate (790 mg, 7.6 mmol) was stirredat reflux for 16 h. The mixture was allowed to cool to RT, and quenchedwith water. The solid precipitate was collected by filtration and rinsedwith a mixture of petroleum ether-ethyl acetate-MeOH (100:10:5) anddried in vacuo to yield the crude product (320 mg, 94.8% yield) as abrown solid. ESI-MS m/z: 354.9 [M+H]⁺.

6-Bromo-4-chloro-7-(2,4-difluorophenyl)-8-fluoroquinazoline

A mixture of 6-bromo-7-(2,4-difluorophenyl)-8-fluoroquinazolin-4-ol (320mg, 0.901 mmol), SOCl₂ (3 mL) and DMF (cat.) was stirred at reflux for 1h. The mixture was allowed to cool to RT and then concentrated in vacuoto yield the desired product as a brown solid which was used directly innext step without further purification

tert-Butyl-4-(6-bromo-7-(2,4-difluorophenyl)-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate

The above obtained crude6-bromo-4-chloro-7-(2,4-difluorophenyl)-8-fluoroquinazoline was added tothe mixture of tert-butyl piperazine-1-carboxylate (344 mg, 1.80 mmol)and DIPEA (585 mg, 4.50 mmol) in dioxane (10 mL). The resulting mixturewas stirred at reflux for 16 h and then was quenched with saturatedNaHCO₃ aqueous solution. The mixture was extracted with dichloromethane.The organic layer was washed with saturated NaHCO₃ aqueous solution andbrine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (ethylacetate/petroleum ether=2:1) to yield the desired product (410 mg, 87%yield, 2 steps) as an off-white solid. ESI-MS m/z: 523.1 [M+H]⁺.

tert-Butyl-4-(7-(2,4-difluorophenyl)-8-fluoro-6-methylquinazolin-4-yl)piperazine-1-carboxylate

To a solution oftert-butyl-4-(6-bromo-7-(2,4-difluorophenyl)-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate(200 mg, 0.382 mmol) and Pd(PPh₃)₄ (44 mg, 0.0382 mmol) in THF (4 mL) atRT under nitrogen atmosphere, dimethylzinc (1.147 mL, 1.147 mmol, 1.0 Min THF) was added. The resulting mixture was stirred at RT for 30 minand then stirred at 50° C. overnight. The mixture was allowed to cool toRT, quenched with saturated NH₄Cl aqueous solution, and extracted withethyl acetate. The organic layer was washed with saturated NaHCO₃solution and brine, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by Prep-HPLC to yield the desired product (90 mg,51.3% yield) as an off-white solid. ESI-MS m/z: 459.2 [M+H]⁺.

1-(4-(7-(2,4-Difluorophenyl)-8-fluoro-6-methylquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

The title compound was prepared fromtert-butyl-4-(7-(2,4-difluorophenyl)-8-fluoro-6-methylquinazolin-4-yl)piperazine-1-carboxylatein two steps according to the procedure described in Example 2. ¹H NMR(400 MHz, DMSO-d6) δ: 8.67 (s, 1H), 7.83 (s, 1H), 7.57-7.47 (m, 2H),7.32-7.29 (m, 1H), 6.84 (dd, J=10.4, 16.8, 1H), 6.18 (dd, J=2.4, 16.8,1H), 5.75 (dd, J=2.0, 10.4, 1H), 3.87-3.77 (m, 8H), 2.26 (s, 3H). ESI-MSm/z: 413.2 [M+H]⁺.

Example 41 Synthesis of1-(4-(7-(2,4-difluorophenyl)-6,8-difluoroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 41 provides an exemplary preparation according to GeneralSynthetic Method Y

2-Bromo-1,3-difluoro-4-nitrobenzene

KNO₃ (5.20 g, 51.80 mmol) was added into a solution of2-bromo-1,3-difluorobenzene (5.0 g, 26.0 mmol) in H₂SO₄ (30 mL) at) 0°C. and stirred at 25° C. for 18 h. The mixture was poured into ice-waterand extracted with ethyl acetate. The organic layer was washed withsaturated NaHCO₃ aqueous solution and brine, dried over Na₂SO₄ andconcentrated to yield the product as a yellow solid (5.0 g, 81% yield).

3-Bromo-2,4-difluoroaniline

To a mixture of 2-bromo-1,3-difluoro-4-nitrobenzene (5 g, 21.01 mmol),AcOH (5.70 g, 94.53 mmol), EtOH (100 mL) and H₂O (60 mL) at RT, ironpowder (5.30 g, 94.53 mmol) was added in portions and the resultingmixture was stirred at RT for 16 h. The mixture was neutralized withNaOH (5 N) solution and then extracted with ethyl acetate. The organiclayer was washed with brine, dried over Na₂SO₄ and concentrated invacuo. The residue was purified by flash column chromatography on silicagel (petroleum) to afford the desired product (1.60 g, 37% yield) as abrown oil.

N-(3-Bromo-2,4-difluorophenyl)-2-(hydroxyimino)acetamide

To a mixture of 3-bromo-2,4-difluoroaniline (1.60 g, 7.69 mmol), Na₂SO₄(9.8 g, 68.77 mmol), 2,2,2-trichloroethane-1,1-diol (1 g, 5.82 mmol) andhydroxylamine hydrochloride (1.1 g, 15.87 mmol), the concentratedsulfuric acid (4 mL) was added. The resulting mixture was stirred at130° C. for 2 h and yellow precipitate was formed. The mixture wascooled to RT. The solid was collected by filtration, rinsed with water,and dried in the air to afford the desired product (1.3 g, 61% yield).

1-(4-(6,8-Difluoro-7-(2,4-difluorophenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

The title compound was prepared fromN-(3-bromo-2,4-difluorophenyl)-2-(hydroxyimino)acetamide according tothe procedure described in Example 30. ¹H NMR (400 MHz, CDCl₃) δ: 8.83(s, 1H), 7.49-7.44 (m, 2H), 7.09-7.00 (m, 2H), 6.63 (dd, J=10.5, 16.9Hz, 1H), 6.39 (dd, J=1.3, 16.8 Hz, 1H), 5.80 (dd, J=1.4, 10.4 Hz, 1H),3.91-3.86 (m, 8H). ESI-MS m/z: 417.2 [M+H]⁺.

Example 42 Synthesis of1-(4-(6-chloro-7-(2,4-difluorophenyl)-8-hydroxyquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 42 provides an exemplary preparation according to GeneralSynthetic Method Z

tert-Butyl4-(7-bromo-6-chloro-8-methoxyquinazolin-4-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(7-bromo-6-chloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate (45mg, 0.10 mmol) in THF (8 mL) at RT, CH₃ONa (17 mg, 0.15 mmol) was addedand the resulting mixture was stirred for 16 h. The mixture was pouredinto ice-water, and extracted with ethyl acetate. The organic layer waswashed with brine, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by Prep-TLC to afford the desired product as awhite solid (32 mg, 70% yield). ESI-MS m/z: 459.1 [M+H]⁺.

tert-Butyl4-(6-chloro-7-(2,4-difluorophenyl)-8-methoxyquinazolin-4-yl)piperazine-1-carboxylate

A mixture oftert-butyl4-(7-bromo-6-chloro-8-methoxyquinazolin-4-yl)piperazine-1-carboxylate(65 mg, 0.14 mmol), 2,4-difluorophenylboronic acid (25 mg, 0.15 mmol),Pd(PPh₃)₄ (16 mg, 0.014 mmol) and Na₂CO₃ (45 mg, 0.42 mmol) in1,4-dioxane/H₂O (8 mL/2 mL) was stirred at 100° C. under argon for 16 h.The mixture was allowed to cool to RT and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel (1%methanol/dichloromethane) to afford the desired product (17 mg, 25%yield) as a white solid. ESI-MS m/z: 491.2 [M+H]⁺.

6-Chloro-7-(2,4-difluorophenyl)-8-methoxy-4-(piperazin-1-yl)quinazoline

To a solution oftert-butyl4-(6-chloro-7-(2,4-difluorophenyl)-8-methoxyquinazolin-4-yl)piperazine-1-carboxylate(22 mg, 0.044 mmol) in dichloromethane (5 mL) at RT, TFA (1 mL) wasadded and the resulting mixture was stirred at RT for 1 h. The mixturewas concentrated in vacuo. The resultant was quenched with NaHCO₃solution, and the aqueous solution was extracted with ethyl acetate. Theorganic layer was washed with brine, dried over Na₂SO₄ and concentratedin vacuo to afford the desired product as a white solid (17 mg, 100%yield).

1-(4-(6-Chloro-7-(2,4-difluorophenyl)-8-methoxyquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

To a solution of the above obtained crude6-chloro-7-(2,4-difluorophenyl)-8-methoxy-4-(piperazin-1-yl)quinazoline(17 mg, 0.0448 mmol) in dichloromethane (10 mL) and Et₃N (14 mg, 0.134mmol) at 0° C., acryloyl chloride (5 mg, 0.05 mmol) was added and theresulting mixture was stirred at 0° C. for 2 h. The mixture was quenchedwith saturated NaHCO₃ aqueous solution, and then extracted with ethylacetate. The organic layer was washed with saturated NaHCO₃ solution andbrine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by Prep-TLC to yield the desired product (9 mg, 47% yield) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ: 8.82 (s, 1H), 7.77 (s, 1H),7.29-7.33 (m, 1H), 6.97-7.06 (m, 2H), 6.61-6.67 (m, 1H), 6.37-6.42 (m,1H), 5.79-5.82 (m, 1H), 3.96 (s, 3H), 3.82-3.92 (m, 8H). ESI-MS m/z:445.2 [M+H]⁺.

1-(4-(6-Chloro-7-(2,4-difluorophenyl)-8-hydroxyquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

To a solution of1-(4-(6-chloro-7-(2,4-difluorophenyl)-8-methoxyquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one(53 mg, 0.119 mmol) in dichloromethane (10 mL) at −78° C. undernitrogen, BBr₃ (298 mg, 1.19 mmol) was added and the resulting mixturewas stirred from at −78° C. to RT for 3 h. The mixture was cooled to−30° C., and NaHCO₃ solution was added. The aqueous solution wasextracted with ethyl acetate. The organic layer was washed with brine,dried over Na₂SO₄ and concentrated in vacuo. The residue was purified byprep-TLC to afford the desired product as a white solid (17 mg, 33%yield). ¹H NMR (400 MHz, DMSO-d6) δ: 8.70 (s, 1H), 7.61 (s, 1H),7.37-7.46 (m, 2H), 7.20-7.24 (m, 1H), 6.80-6.87 (m, 1H), 6.15-6.20 (m,1H), 5.72-5.76 (m, 1H), 3.76-3.86 (m, 8H). ESI-MS m/z: 431.1 [M+H]⁺.

Example 43 Synthesis of1-(4-(6-chloro-7-(2-fluoro-6-hydroxyphenyl)-5-(trifluoromethyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 43 provides an exemplary preparation according to GeneralSynthetic Method AA

5-Bromo-2-methyl-1-nitro-3-(trifluoromethyl)benzene

2-Methyl-1-nitro-3-(trifluoromethyl)benzene (1 g, 4.87 mmol) wasdissolved in concentrated sulfuric acid (15 mL),1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (836 mg, 2.92 mmol) wasadded in portions and the resulting mixture was stirred at RT for 2 h.The reaction mixture was poured into ice water, stirred for 10 min, andthen extracted with ethyl acetate. The combined organic layer was washedwith water, saturated NaHCO₃ solution and brine, dried over Na₂SO₄, andconcentrated in vacuo to afford the crude product (1.1 g).

5-Bromo-2-(bromomethyl)-1-nitro-3-(trifluoromethyl)benzene

NBS (12.6 g, 70.61 mmol) was added into a solution of5-bromo-2-methyl-1-nitro-3-(trifluoromethyl)benzene (19 g, 67.25 mmol)and BPO (1.63 g, 6.73 mmol) in CCl₄ (200 mL). The mixture was stirred atreflux under argon for 18 h. The resulting mixture was concentrated andthe residue was purified by column chromatography eluting with petroleumether to yield the product (14 g, 58% yield).

4-Bromo-2-nitro-6-(trifluoromethyl)benzaldehyde

To a mixture of5-bromo-2-(bromomethyl)-1-nitro-3-(trifluoromethyl)benzene (14 g, 38.88mmol) and 4 Å molecular sieves (25 g) in MeCN (120 mL) at RT,N-methylmorpholine N-oxide (9.2 g, 82.14 mmol) was added and theresulting mixture was stirred under argon for 1.5 h. The mixture wasdiluted with ethyl acetate and filtered. The filtrate was washed withH₂O, 1 N HCl and brine, dried over Na₂SO₄ and concentrated in vacuo togive the desired product (4.1 g, 37% yield) which was used in the nextstep without further purification.

4-Bromo-2-fluoro-6-nitrobenzoic acid

To a solution of 4-bromo-2-nitro-6-(trifluoromethyl)benzaldehyde (4.1 g,13.75 mmol) in a mixture of THF, H₂O and t-BuOH at −5° C., NaClO₂ (4.97g, 55.03 mmol) and NaH₂PO₄ (6.6 g, 55.03 mmol) were added. The mixturewas treated with 2-methylbut-2-ene (6.75 g, 96.25 mmol) dropwise. Thereaction was stirred at 0° C. for 1.5 h and concentrated in vacuo. Theresidue was diluted with water, acidified with 2 N HCl to pH 4-5 andthen extracted with ethyl acetate. The organic layer was washed withwater and brine, dried over Na₂SO₄, and concentrated to afford crudeproduct (4.4 g) which used in next step directly.

2-Amino-4-bromo-6-(trifluoromethyl)benzoic acid

To a solution of 4-bromo-2-fluoro-6-nitrobenzoic acid (4.4 g, 12.9 mmol)in a mixture of AcOH (40 mL) and H2O (20 mL), Fe (3.6 g, 64.5 mmol) wasadded and the resulting mixture was stirred at RT for 2 h. The mixturewas poured into water, and extracted with EtOAc. The organic layer waswashed with water and brine, dried over Na₂SO₄, and concentrated invacuo to afford the target product (3.1 g) without further purification.

Methyl 2-amino-4-bromo-6-(trifluoromethyl)benzoate

Cs₂CO₃ (4.82 g, 14.79 mmol) was added into a solution of2-amino-4-bromo-6-(trifluoromethyl)benzoic acid (2.8 g, 9.86 mmol) inDMF (30 mL), and the resulting mixture was stirred at RT for 40 min. Tothis mixture, CH₃I (1.4 g, 9.86 mmol) was added dropwise and stirringwas continued at RT for 16 h. The mixture was poured into water andextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (ethylacetate/petroleum ether=1:10) to yield the desired product (2.9 g, 97%yield) as a yellow solid.

Methyl 6-amino-4-bromo-3-chloro-2-(trifluoromethyl)benzoate

To a solution of methyl 2-amino-4-bromo-6-(trifluoromethyl)benzoate (2.8g, 9.39 mmol) in isopropyl alcohol (45 mL) at RT, NCS (1.51 g, 11.28mmol) was added in portions and the resulting mixture was stirred atreflux for 16 h. The mixture was allowed to coo, to RT and the residuewas purified by flash column chromatography on silica (ethylacetate/petroleum ether=1:20) to afford the desired product (860 mg, 27%yield).

1-(4-(6-Chloro-7-(2-fluoro-6-hydroxyphenyl)-5-(trifluoromethyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

The title compound was prepared from methyl6-amino-4-bromo-3-chloro-2-(trifluoromethyl)benzoate according to theprocedure described in Example 30. ¹H NMR (400 MHz, DMSO-d6) δ:10.29 (s,1H), 8.50 (s, 1H), 7.93 (s, 1H), 7.35-7.33 (m, 1H), 6.91-6.89 (m, 1H),6.83-6.76 (m, 1H), 6.17-6.12 (dd, J=2.0, 16.8 Hz, 1H), 5.74-5.70 (dd,J=2.4, 10.4 Hz, 1H), 3.88 (s, 4H), 3.66-3.64 (m, 2H), 3.46 (m, 2H).ESI-MS m/z: 481.3 [M+H]⁺.

Example 44 Synthesis of4-(4-acryloylpiperazin-1-yl)-6-chloro-7-(5-methyl-1H-indazol-4-yl)quinolin-2(1H)-one

Example 44 provides an exemplary preparation according to GeneralSynthetic Method AB

7-Bromo-4,6-dichloroquinoline N-oxide

To a stirred solution of 7-bromo-4,6-dichloroquinoline (500 mg, 1.82mmol) in DC under argon, UHP (359 mg, 3.82 mmol) was added. The mixturewas cooled to 0° C., and TFA (415 mg, 3.64 mmol) was added. Theresulting mixture was stirred at RT for 16 h. The mixture was washedwith brine, dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to afford the desired product (450 mg, 85% yield). ESI-MS m/z:292.3 [M+H]⁺.

7-Bromo-2,4,6-trichloroquinoline

The mixture of 7-bromo-2,4,6-trichloroquinolin N-oxide (450 mg, 1.55mmol) in POCl₃ (20 mL) was stirred at reflux for 1 h. The mixture wasconcentrated to dryness and the residue was partitioned between waterand ethyl acetate. The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by flashcolumn chromatography on silica gel (ethyl acetate/petroleum ether=1:5)to afford the desired product (400 mg, 84% yield) as solid. ESI-MS m/z:310.1 [M+H]⁺.

7-Bromo-4,6-dichloroquinolin-2(1H)-one

The mixture of 7-bromo-2,4,6-trichloroquinolin (400 mg, 1.29 mmol) in20% H₂SO₄ (10 mL) and dioxane (10 mL) was stirred at 140° C. for 8 h.The mixture was quenched with water and extracted with ethyl acetate.The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to afford the desired product (250 mg, 66% yield)as solid. ESI-MS m/z: 292.1 [M+H]⁺.

tert-Butyl4-(7-bromo-6-chloro-1,2-dihydro-2-oxoquinolin-4-yl)piperazine-1-carboxylate

A mixture of 7-bromo-4,6-dichloroquinolin-2(1H)-one (250 mg, 0.856 mmol)and tert-butyl piperazine-1-carboxylate (796 mg, 4.28 mmol) in n-BuOH(10 mL) was stirred at 150° C. in a sealed tube for 24 h. The mixturewas quenched with water and extracted with ethyl acetate. The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated invacuo. The residue was purified by flash column chromatography on silicagel (dichloromethane/MeOH=30:1) to afford the desired product (180 mg,47% yield) as solid. ESI-MS m/z: 442.1 [M+H]⁺.

4-(4-Acryloylpiperazin-1-yl)-6-chloro-7-(5-methyl-1H-indazol-4-yl)quinolin-2(1H)-one

The title compound was prepared from tert-butyl4-(7-bromo-6-chloro-1,2-dihydro-2-oxoquinolin-4-yl)piperazine-1-carboxylateaccording to the procedure described in Examples 2. ¹H NMR (400 MHz,DMSO-d6) δ: 13.15 (s, 1H), 11.60 (s, 1H), 7.86 (s, 1H), 7.55 (m, 1H),7.52 (s, 1H), 7.35 (m, 1H), 7.25 (s, 1H), 6.90-6.84 (dd, J=12.0, 16.4Hz, 1H), 6.20-6.15 (dd, J=2.4, 16.8 Hz, 1H), 6.02 (s, 1H), 5.77-5.74(dd, J=2.1, 10.0 Hz, 1H), 3.86-3.83 (m, 4H), 3.13 (m, 4H), 2.17 (s, 3H).ESI-MS m/z: 450.2 [M+H]⁺.

Example 45 Synthesis of1-(4-(6-chloro-2-(2-(dimethylamino)ethylamino)-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 44 provides an exemplary preparation according to GeneralSynthetic Method AC

7-Bromo-6-chloro-8-fluoroquinazoline-2,4(1H,3H)-dione

A mixture of methyl 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (10.0g, 39.9 mmol) and urea (12 g, 199.6 mmol) was stirred at 200° C. for 3h. The mixture was allowed to cool to RT, triturated with ethyl acetateand dried to afford the crude product (13 g) as a brown solid.

7-Bromo-2,4,6-trichloro-8-fluoroquinazoline

The mixture of 7-bromo-6-chloro-8-fluoroquinazoline-2,4(1H,3H)-dione (13g, 44.5 mmol) in POCl₃ (200 mL) and DIPEA (20 mL) was stirred at refluxfor 16 h. The mixture was allowed to cool to RT and concentrated invacuo to remove POCl₃. The residue was purified by flash chromatographyon silica gel (5% ethyl acetate/petroleum ether) and then washed by HCl(1M) to afford the product (10.4 g, 74% yield) as a yellow solid.

4-(7-Bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate

To a solution of 7-bromo-2,4,6-trichloro-8-fluoroquinazoline (10.4 g,33.3 mmol) and DIEA (29 mL, 167 mmol) in 1,4-dioxane (100 mL) at RT,tert-butyl piperazine-1-carboxylate (6.2 g, 33.3 mmol) was added. Theresulting mixture was stirred at 50° C. for 20 min. The mixture wasallowed to cool to RT and partitioned between water and ethyl acetate.The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated. The residue was purified by flash column chromatography onsilica gel (MeOH/dichloromethane=1:200) to afford the desired product (6g, 40% yield) as a yellow solid. ESI-MS m/z: 447.2 [M+H]⁺.

tert-Butyl4-(2-(2-(dimethylamino)ethylamino)-7-bromo-6-chloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate

To a stirred solution of tert-butyl4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate (300 mg, 0.63 mmol) in propan-2-ol (10 mL),DIEA (243 mg, 1.88 mmol) and N¹,N¹-dimethylethane-1,2-diamine (166 mg,1.88 mmol) were added and the resulting mixture was stirred at 95° C.overnight. The mixture was allowed to cool to RT, and partitionedbetween water and ethyl acetate. The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by flash column chromatography on silica gel (1-5%MeOH/dichoromethane) to afford the desired product (230 mg, 69% yield)as a white solid. ESI-MS m/z: 531.3 [M+H]⁺.

1-(4-(2-(2-(Dimethylamino)ethylamino)-6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

The title compound was prepared from tert-butyl4-(2-(2-(dimethylamino)ethylamino)-6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)piperazine-1-carboxylatein three steps following the procedure described in Example 2.

¹H NMR (400 MHz, DMSO-d6) δ: 13.16 (s, 1H), 7.81 (s, 1H), 7.56-7.58 (m,2H), 7.37-7.39 (m, 1H), 6.96-7.32 (m, 1H), 6.82-6.89 (m, 1H), 6.17 (dd,J=2.2, 16.5 Hz, 1H), 5.74 (dd, J=2.1, 10.3 Hz, 1H), 3.72-3.84 (m, 8H),3.45 (m, 2H), 2.42-2.45 (m, 2H), 2.17-2.21 (m, 9H). ESI-MS m/z: 537.4[M+H]⁺.

Example 46 Synthesis of1-(4-(6-chloro-2-((dimethylamino)methyl)-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 46 provides an exemplary preparation according to GeneralSynthetic Method AD

Methyl 2-amino-4-bromo-5-chloro-3-fluorobenzoate

A mixture of 2-amino-4-bromo-5-chloro-3-fluorobenzoic acid (1.0 g, 3.746mmol) in CH₃OH (30 mL), SOCl₂ (4.457 g, 37.46 mmol) was added dropwiseand the resulting mixture was stirred at 100° C. for 16 h. The solventwas removed and the residue was dissolved in ethyl acetate. The organiclayer was washed with saturated NaHCO₃ aqueous solution and brine, driedover Na₂SO₄ and concentrated. The residue was purified by columnchromatography (ethyl acetate/petroleum ether=1:10) to afford theproduct as a pink solid (848 mg, 81% yield).

7-Bromo-6-chloro-2-(chloromethyl)-8-fluoroquinazolin-4-ol

A mixture of methyl 2-amino-4-bromo-5-chloro-3-fluorobenzoate (500 mg,1.779 mmol) and 2-chloroacetonitrile (667 mg, 8.895 mmol) in dioxane (30mL) was bubbled with HCl gas at RT for 1 h, and the resulting mixturewas stirred at 80° C. for 16 h. The mixture was allowed to cool to RTand then Et₂O (20 mL) was added to it. After stirring for 1 h, themixture was filtered and the white solid was collected. The white solidwas dissolved in ethyl acetate and washed with saturated NaHCO₃ aqueoussolution and brine. The organic layer was dried over Na₂SO₄ andconcentrated in vacuo to afford the product as a white solid (605 mg,104% yield).

7-Bromo-4,6-dichloro-2-(chloromethyl)-8-fluoroquinazoline

A mixture of 7-bromo-6-chloro-2-(chloromethyl)-8-fluoroquinazolin-4-ol(300 mg, 0.925 mmol) and DIEA (3 mL) in POCl₃ (30 mL) was stirred at130° C. for 16 h.

The mixture was concentrated in vacuo and azeotroped with toluene. Theresidue was purified by column chromatography on silica gel (ethylacetate/petroleum ether=1:6) to afford the product as an orange colorsolid (320 mg, 100% yield).

tert-Butyl-4-(7-bromo-6-chloro-2-(chloromethyl)-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate

A mixture of 7-bromo-4,6-dichloro-2-(chloromethyl)-8-fluoroquinazoline(320 mg, 0.936 mmol) and tert-butyl piperazine-1-carboxylate (260 mg,1.397 mmol) in i-PrOH (30 mL) was stirred at 75° C. for 1 h. The mixturewas concentrated in vacuo. The residue was dissolved in ethyl acetate,washed with saturated NaHCO₃ aqueous solution and brine, dried overNa₂SO₄ and concentrated. The residue was purified by columnchromatography on silica gel (ethyl acetate/petroleum ether=1:4) toafford the product as a yellow solid (422 mg, 92% yield). ESI-MS m/z:495.2 [M+H]⁺.

tert-Butyl-4-(7-bromo-6-chloro-2-((dimethylamino)methyl)-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate

A mixture of 7-bromo-4,6-dichloro-2-(chloromethyl)-8-fluoroquinazoline(422 mg, 0.857 mmol) and dimethylamine (2.0 M in THF, 4.7 mL) wasstirred at 80° C. for 16 h. The mixture was diluted with ethyl acetate,washed with saturated NaHCO₃ aqueous solution and brine, dried overNa₂SO₄ and concentrated. The residue was purified by columnchromatography on silica gel (dichloromethane/MeOH=30:1) to afford theproduct as an orange color thick oil (437 mg, 100% yield). ESI-MS m/z:504.2 [M+H]⁺.

1-(4-(6-Chloro-2-((dimethylamino)methyl)-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

The title compound was prepared fromtert-butyl-4-(7-bromo-6-chloro-2-((dimethylamino)methyl)-8-fluoroquinazolin-4-yl)piperazine-1-carboxylatein three steps cording to the procedure described in Example 2. ¹H NMR(400 MHz, DMSO-d6) δ: 13.24 (s, 1H), 8.15 (s, 1H), 7.62 (m, 2H), 7.42(m, 1H), 6.88 (dd, J=10.4 Hz, J₂=16.8 Hz, 1H), 6.22 (dd, J=2.4 Hz,J₂=17.2 Hz, 1H), 5.78 (dd, J=2.4 Hz, J₂=10.4 Hz, 1H), 4.33 (s, 2H), 4.05(m, 8H), 2.82 (s, 6H), 2.17 (s, 3H). ESI-MS m/z: 508.2[M+H]⁺.

Example 47 Synthesis of1-(4-(6-chloro-5-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 47 provides an exemplary preparation according to GeneralSynthetic Method AE

5-Bromo-2-methyl-1,3-dinitrobenzene

To a solution of 2-methyl-1,3-dinitrobenzene (10 g, 54.91 mmol) inconcentrated sulfuric acid (150 mL),1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (9.42 g, 32.94 mmol) wasadded and the resulting mixture was stirred at RT for 2 h. The mixturewas poured into ice-water, stirred for 10 min, and then extracted withethyl acetate. The combined organic layer was washed with water,saturated NaHCO₃ solution and brine, dried over Na₂SO₄, concentrated toafford the crude product (15 g).

5-Bromo-2-methyl-3-nitroaniline

To a mixture of 5-bromo-2-methyl-1,3-dinitrobenzene (11.2 g, 42.91 mmol)and pyridine (15.6 g, 197.47 mmol) in EtOH (230 mL), (NH₄)₂S (39 g, 22%in water) was added dropwise over 1 h. The mixture was concentrated invacuo. The residue was diluted with water and stirred at 0° C. for 10min. The solid was collected by filtration, rinsed with water, and driedunder vacuum to afford 10.5 g crude product.

5-Bromo-1-fluoro-2-methyl-3-nitrobenzene

To a mixture of 5-bromo-2-methyl-3-nitroaniline (9.5 g, 41.12 mmol) andBF₃-Et₂O (8.7 g, 61.67 mmol) in THF (30 mL) and dichloromethane (60 mL)at −10 OC, tert-butyl nitrite (5.1 g, 49.34 mmol) was added dropwise andthe resulting mixture was stirred at 0° C. for 1.5 h. The mixture wasdiluted with dichloromethane (200 mL) and stirred for 5 min. The solidwas collected by filtration and dried in vacuo. The crude product wasmixed with sand and heated to 120° C. for 40 min. The mixture wasallowed to cool to RT, and then rinsed with dichloromethane. The organiclayer was concentrated in vacuo and the residue was purified by columnchromatography on silica gel (petroleum ether) to yield the product (3.6g, 37.5% yield).

5-Bromo-2-(bromomethyl)-1-fluoro-3-nitrobenzene

To a solution of 5-bromo-1-fluoro-2-methyl-3-nitrobenzene (11.2 g, 47.86mmol) and BPO (1.2 g, 4.79 mmol) in CCl₄ (150 mL), NBS (10.2 g, 57.43mmol) was added and the resulting mixture was stirred at reflux underargon for 18 h. The mixture was concentrated in vacuo and the residuewas purified by column chromatography on silica gel (petroleum ether) toyield the product (11.7 g, 78% yield).

4-Bromo-2-fluoro-6-nitrobenzaldehyde

To a mixture of 5-bromo-2-(bromomethyl)-1-fluoro-3-nitrobenzene (10 g,41.28 mmol) and 4 Å molecular sieves (25 g) in MeCN (120 mL) at RT,N-methylmorpholine N-oxide (9.2 g, 82.14 mmol) was added and theresulting mixture was stirred under argon for 1.5 h. The mixture wasdiluted with ethyl acetate and filtered. The filtrate was washed withH₂O, 1 N HCl and brine. The organic layer was dried over Na₂SO₄ andconcentrated in vacuo to afford the product (6.82 g, 67%) which was usedin the next step without further purification.

4-Bromo-2-fluoro-6-nitrobenzoic acid

To a solution of 4-bromo-2-fluoro-6-nitrobenzaldehyde (4 g, 16.13 mmol)in THF-H₂O-t-BuOH at −5° C., NaClO₂ (5.83 g, 64.51 mmol) and NaH₂PO₄(7.74 g, 64.51 mmol) were added followed by addition of2-methylbut-2-ene (7.92 g, 112.91 mmol) dropwise. The mixture wasstirred at 0° C. for 1.5 h and concentrated in vacuo. The residue wasdiluted with water and acidified with 2 N HCl to pH 4-5. The mixture wasextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over Na₂SO₄, and concentrated in vacuo to afford thecrude product (4.8 g) which was used in the next step directly.

2-Amino-4-bromo-6-fluorobenzoic acid

To a solution of 4-bromo-2-fluoro-6-nitrobenzoic acid (4.8 g, 18.18mmol) in AcOH (40 mL) and H₂O (20 mL), Fe (5.1 g, 90.9 mmol) was addedand the resulting mixture was stirred at RT for 2 h. The mixture waspoured into water, and extracted with ethyl acetate. The organic layerwas washed with water and brine, dried over Na₂SO₄, and concentrated invacuo to afford the crude product (2.75 g) which was used in the nextstep without further purification.

Methyl 2-amino-4-bromo-6-fluorobenzoate

To a solution of 2-amino-4-bromo-6-fluorobenzoic acid (2.75 g, 11.75mmol) in DMF (40 mL), Cs₂CO₃ (5.74 g, 17.63 mmol) was added and theresulting mixture was stirred at RT for 40 min. To this mixture, CH₃I(1.75 g, 12.33 mmol) was added dropwise and the resulting mixture wasstirred at RT for 16 h. The mixture was poured into water and extractedwith ethyl acetate. The organic layer was washed with water and brine,dried Na₂SO₄, and concentrated in vacuo. The residue was purified byflash column chromatography on silica gel (ethyl acetate/petroleumether=1:15) to yield the desired product (2.32 g, 80% yield) as a yellowsolid.

Methyl 6-amino-4-bromo-3-chloro-2-fluorobenzoate

To a solution of methyl 2-amino-4-bromo-6-fluorobenzoate (3.8 g, 15.48mmol) in isopropyl alcohol (45 mL) at RT, NCS (2.2 g, 16.25 mmol) wasadded in portions and the resulting mixture was stirred at reflux for 4h. The mixture was concentrated in vacuo and the residue was purified byflash column chromatography on silica gel (ethyl acetate/petroleumether=1:30) to yield the desired product (1.68 g, 38% yield).

6-Amino-4-bromo-3-chloro-2-fluorobenzoic acid

To a solution of methyl 6-amino-4-bromo-3-chloro-2-fluorobenzoate (200mg, 0.71 mmol) in a mixture of THF (5 mL), H₂O (2 mL) and MeOH (1 mL),LiOH.H₂O (297 mg, 7.08 mmol) was added. The resulting mixture wasstirred at RT for 2 h. The mixture was concentrated in vacuo. Theresidue was diluted with water and acidified with 2 N HCl to pH 4-5. Themixture was extracted with ethyl acetate. The organic layer was washedwith water and brine, dried over Na₂SO₄, and concentrated in vacuo toafford the desired product (189 mg, 100% yield).

1-(4-(6-Chloro-5-fluoro-7-(2-fluoro-6-hydroxyphenyl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

The title compound was prepared from6-amino-4-bromo-3-chloro-2-fluorobenzoic acid according to the proceduredescribed in Example 30. ¹H NMR (400 MHz, DMSO-d6) δ: 10.22 (s, 1H),8.66 (s, 1H), 7.65 (s, 1H), 7.31-7.37 (m, 1H), 6.88-6.79 (m, 3H),6.19-6.14 (dd, J=2.0, 16.8 Hz, 1H), 5.75-5.72 (dd, J=2.4, 10.4 Hz, 1H),3.78-3.70 (m, 8H). ESI-MS m/z: 431.4 [M+H]⁺.

Example 48 Synthesis of1-(4-(6-chloro-7,8′-biquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 48 provides an exemplary preparation according to GeneralSynthetic Method AF

(4-(4-(tert-Butoxycarbonyl)piperazin-1-yl)-6-chloroquinazolin-7-yl)boronicacid

The mixture of tert-butyl4-(7-bromo-6-chloroquinazolin-4-yl)piperazine-1-carboxylate (1.45 g, 1.0eq), bis(pinacolato)diboron (2.02 g, 2.3 eq.), and potassium acetate(1.66 g, 5.0 eq) in dioxane was degassed via nitrogen gas. After addingPdCl₂(dppf) (306 mg, 0.11 eq.), the reaction mixture was degassed againvia nitrogen gas. The resulting mixture was stirred at 120° C. for 2 h.The mixture was allowed to cool to RT, diluted with EtOAc, washed withwater, dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by column chromatography on silica gel to afford the desiredproduct in 43% yield.

tert-Butyl 4-(6-chloro-[7,8′-biquinazolin]-4-yl)piperazine-1-carboxylate

To a solution of(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-chloroquinazolin-7-yl)boronicacid (108 mg, 1.0 eq.) in dioxane (4 mL) in the sealed tube,8-bromoquinazoline (79 mg, 1.3 eq.), PdCl₂(dppf) (26 mg, 0.1 eq.) andaqueous Na₂CO₃ (1M, 2 mL) we added. The resulting mixture was stirred at120° C. for 5 min in the Microwave Reactor. After cooling down, it wasfiltered and partitioned between EtOAc and water. The organic layer wasdried over Na₂SO₄ and concentrated in vacuo. The residue was useddirectly in the next step.

1-(4-(6-chloro-[7,8′-biquinazolin]-4-yl)piperazin-1-yl)prop-2-en-1-one

TFA (1 mL) was added into above obtained tert-butyl4-(6-chloro-[7,8′-biquinazolin]-4-yl)piperazine-1-carboxylate (131 mg,1.0 eq.) in DCM (10 mL). The reaction mixture was stirred at RT for 1 h.The mixture was concentrated in vacuo. To a solution of above obtainedcrude compound in Et₃N (0.5 mL, 13.0 eq) and dichloromethane (10 mL),acryloyl chloride (0.062 mL, 2.8 eq.) was added and the resultingmixture was stirred at RT for 1.5 h. The mixture was concentrated invacuo to remove the DCM. The residue was dissolved in EtOAC. It waswashed with water, dried over Na₂SO₄ and concentrated in vacuo. Aftercolumn purification, the desired product was obtained in 44% yield overthree steps from(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-chloroquinazolin-7-yl)boronicacid. ¹H NMR (500 MHz, DMSO-d6) δ: 9.73 (s, 1H), 9.26 (s, 1H), 8.700 (s,1H), 8.32 (dd, J=8, 1.5 Hz, 1H), 8.20 (s, 1H), 8.09 (dd, J=7, 1.5 Hz,1H), 7.92 (t, J=8 Hz, 1H), 7.891 (s, 1H), 6.84 (dd, J=17, 10.5 Hz, 1H),6.18 (dd, J=17, 2.5 Hz, 1H), 5.75 (dd, J=10.5, 2.5 Hz, 1H), 3.92-3.79(m, 8H). ESI-MS m/z: 431.1 [M+H]⁺.

Example 49 Synthesis of1-(4-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(thiazol-5-yl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 49 provides an exemplary preparation according to GeneralSynthetic Method AG

tert-Butyl4-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(thiazol-5-yl)quinazolin-4-yl)piperazine-1-carboxylate

5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (67 mg, 1.1eq.) and tetrakis (158 mg, 0.5 eq.) were added into tert-butyl4-(7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate(133 mg, 1.0 eq.) in dioxane (6 mL) and aqueous Na₂CO₃ (1 M, 3 mL) inthe sealed tube. The reaction mixture was stirred at 120° C. in theMicrowave Reactor for 15 min. After cooling down, into this mixture(5-methyl-1H-indazol-4-yl)boronic acid (267 mg, 5.1 eq.), tetrakis (164mg, 0.5 eq.), 4 mL of dioxane, and 2 mL of aqueous Na₂CO₃ (1M) wereadded. The resulting mixture was stirred at 120° C. in the MicrowaveReactor for 45 min. After cooling down, it was filtered and partitionedbetween EtOAc and water. The organic layer was dried over Na₂SO₄, andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (dichloromethane/methanol=10:1) to affordthe desired product (88 mg, 55% yield) as a solid. ESI-MS m/z: 580[M+H]⁺.

1-(4-(6-Chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(thiazol-5-yl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

The title compound was prepared from tert-butyl4-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)-2-(thiazol-5-yl)quinazolin-4-yl)piperazine-1-carboxylatein two steps according to the procedure described in Example 46. ¹H NMR(500 MHz, DMSO-d6) δ: 13.19 (s, 1H), 9.22 (s, 1H), 8.70 (s, 1H), 8.12(s, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.59 (s, 1H), 7.41 (d, J=8.5 Hz, 1H),6.84 (dd, J=17, 10.5 Hz, 1H), 6.18 (dd, J=17, 2.5 Hz, 1H), 5.76 (dd,J=10.5, 2.5 Hz, 1H), 4.06-3.82 (m, 8H), 2.18 (s, 3H). ESI-MS m/z: 534.1[M+H]⁺.

Example 50 Synthesis of1-(4-(6-chloro-8-fluoro-7-(3-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

Example 50 provides an exemplary preparation according to GeneralSynthetic Method AH

1-(4-(6-chloro-8-fluoro-7-(3-fluoro-5-methyl-1H-indazol-4-yl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

A mixture of1-(4-(6-chloro-8-fluoro-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one(45.1 mg, 0.1 mmol) and Selectfluor (53 mg, 0.15 mmol) in acetonitrile(5 mL) was stirred at 120° C. for 2 h. The mixture was allowed to coolto RT and partitioned between DCM and water. The organic layer was driedover Na₂SO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel via Isolera One (MeOH/DCM=0-5%) toafford the desired product (4.4 mg). ¹H NMR (500 MHz, CDCl₃) δ: 1H NMR(CDCl₃): 8.84 (s, 1H), 7.88 (s, 1H), 7.40-7.46 (m, 2H), 6.63 (dd, J=8.4,13.2 Hz, 1H), 6.40 (d, J=13.6 Hz, 1H), 5.78 (d, J=8.4 Hz, 1H), 3.75-4.01(m, 8H), 2.24 (s, 1H). ESI-MS m/z: 469.1 [M+H]⁺.

Example 51 Synthesis of4-(4-acryloylpiperazin-1-yl)-6-chloro-8-fluoro-7-(3-hydroxynaphthalen-1-yl)quinazoline-2-carbonitrile

tert-Butyl4-(2-(acetoxymethyl)-7-bromo-6-chloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate

A mixture of tert-butyl4-(7-bromo-6-chloro-2-(chloromethyl)-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate(288 mg, 0.59 mmol) in DMSO (10 mL), NaOAc (143 mg, 1.75 mmol) was addedand the resulting mixture was stirred at 80° C. for 2 h. The mixture waspartitioned between ethyl acetate and water. The organic layer waswashed with sat. NaHCO₃ and brine, dried over Na₂SO₄ and concentrated invacuo. The residue was purified by column chromatography on silica gel(ethyl acetate/petroleum ether=1:2) to afford the product (306 mg, 100%yield). ESI-MS m/z: 519.2 [M+H]⁺.

tert-Butyl4-(7-bromo-6-chloro-8-fluoro-2-(hydroxymethyl)quinazolin-4-yl)piperazine-1-carboxylate

A mixture of tert-butyl4-(2-(acetoxymethyl)-7-bromo-6-chloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate(306 mg, 0.59 mmol), LiOH.H₂O (99 mg, 2.64 mmol) in THF (30 mL) and H₂O(10 mL) was stirred at RT for 1 h. The mixture was extracted with ethylacetate. The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to afford the product (286 mg, 100% yield). ESI-MSm/z: 477.2 [M+H]⁺.

tert-Butyl4-(7-bromo-6-chloro-8-fluoro-2-formylquinazolin-4-yl)piperazine-1-carboxylate

A mixture of tert-butyl 4-(7-bromo-6-chloro-8-fluoro-2-(hydroxymethyl)quinazolin-4-yl)piperazine-1-carboxylate (286 mg, 0.60 mmol) and MnO₂(523 mg, 6.01 mmol) in dichloromethane (30 mL) was stirred at 60° C. for16 h. The mixture was purified by column chromatography on silica gel(ethyl acetate/petroleum ether=1:1) to afford the product as an orangecolor solid (212 mg, 74.5% yield). ESI-MS m/z: 505.2 [M+H]⁺.

7-Bromo-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-chloro-8-fluoroquinazoline-2-carboxylicacid

To a mixture of tert-butyl4-(7-bromo-6-chloro-8-fluoro-2-formylquinazolin-4-yl)piperazine-1-carboxylate (212 mg, 0.45 mmol) in THF (10 mL), t-BuOH (10mL), DCM (5 mL) and H₂O (10 mL) at 0° C., NaH₂PO₄ (215 mg, 1.79 mmol)and NaClO₂ (162 mg, 1.79 mmol) were added and resulting mixture wasstirred at 0° C. for 1 h. To this mixture, 2-methylbut-2-ene (219 mg,3.13 mmol) was added and stirring was continued for 1 h. The mixture wasconcentrated in vacuo and the residue was diluted with 1M HCl (30 mL)and extracted with ethyl acetate. The organic layer was washed withbrine, dried over Na₂SO₄ and concentrated in vacuo to afford the crudeproduct as a yellow solid (257 mg) which was used in the next stepdirectly withought purification. ESI-MS m/z: 489.1 [M+H]⁺.

tert-Butyl4-(7-bromo-2-carbamoyl-6-chloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate

To a mixture of7-bromo-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-6-chloro-8-fluoroquinazoline-2-carboxylicacid (257 mg, 0.53 mmol), NH₄Cl (112 mg, 2.10 mmol), BOP (464 mg, 1.05mmol) in DMF (10 mL) at RT, DIEA (271 mg, 2.10 mmol) in DCM (5 mL) wasadded dropwise. The mixture was stirred for 1 h. The mixture wasextracted with ethyl acetate, washed with sat.NaHCO₃ and brine. Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel(dichloromethane/MeOH=40:1) to afford the product as a yellow solid (163mg, 63.5% yield). ESI-MS m/z: 490.1 [M+H]⁺.

tert-Butyl4-(2-carbamoyl-6-chloro-8-fluoro-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)piperazine-1-carboxylate

A mixture of tert-butyl4-(7-bromo-2-carbamoyl-6-chloro-8-fluoroquinazolin-4-yl)piperazine-1-carboxylate (80 mg, 0.16 mmol),(3-hydroxynaphthalen-1-yl)boronic acid (34 mg, 0.18 mmol), Na₂CO₃ (86mg, 0.82 mmol), Pd(PPh₃)₄ (19 mg, 0.016 mmol) in dioxane (15 mL) and H₂O(5 mL) was stirred at 100° C. for 16 h. The mixture was partitionedbetween ethyl acetate and water. The organic layer was washed withsat.NaHCO₃ and brine, dried over Na₂SO₄ and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel(dichloromethane/MeOH=30:1) to afford the product as a yellow solid (35mg, 40.2% yield). ESI-MS m/z: 552.2 [M+H]⁺.

4-(4-Acryloylpiperazin-1-yl)-6-chloro-8-fluoro-7-(3-hydroxynaphthalen-1-yl)quinazoline-2-carboxamide

A mixture oftert-butyl-4-(2-carbamoyl-6-chloro-8-fluoro-7-(3-hydroxynaphthalen-1-yl)quinazolin-4-yl)piperazine-1-carboxylate(35 mg, 0.066 mmol) in dichloromethane (10 mL) and CF₃COOH (2 mL) wasstirred at R.T. for 0.5 h. The mixture was concentrated in vacuo. Theresidue was dissolved in dichloromethane (20 mL) and Et₃N (32 mg, 0.317mmol). The mixture was stirred at −78° C. and acryloyl chloride (5.4 mg,0.063 mmol) in dichloromethane (0.8 mL) was added dropwise. The mixturewas stirred at −78° C. for 5 min and quenched with sat.NaHCO₃. Themixture was extracted with dichloromethane. The organic layer was driedover Na₂SO₄ and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (dichloromethane/MeOH=40:1 to 15:1)to afford the product as a white solid (33 mg). ESI-MS m/z: 506.2[M+H]⁺.

4-(4-Acryloylpiperazin-1-yl)-6-chloro-7-(3-hydroxynaphthalen-1-yl)quinazoline-2-carbonitrile

To a stirred mixture of4-(4-acryloylpiperazin-1-yl)-6-chloro-7-(3-hydroxynaphthalen-1-yl)quinazoline-2-carboxamide (33 mg, 0.065 mmol) and Et₃N (33 mg, 0.326mmol) in dichloromethane (20 mL) at RT, (CF₃CO)₂O (68 mg, 0.326 mmol)was added and the resulting mixture was stirred for 0.5 h. The mixturewas quenched with sat.NaHCO₃ and extracted with dichloromethane. Theorganic layer was washed with brine, dried over Na₂SO₄ and concentratedin vacuo. The residue was purified by column chromatography on silicagel (dichloromethane/MeOH=40:1) to afford the product as a white solid(6 mg, 18.8% yield). ¹H NMR (400 MHz, DMSO-d6) δ: 10.11 (s, 1H), 8.21(s, 1H), 7.84 (m, 2H), 7.48-7.10 (m, 5H), 6.86 (dd, J=10.4 Hz, J=16.8Hz, 1H), 6.22 (dd, J=2.0 Hz, J=16.4 Hz, 1H), 5.78 (dd, J=2.4 Hz, J=10.8Hz, 1H), 4.10 (m, 4H), 3.89 (m, 4H). ESI-MS m/z: 488.2 [M+H]⁺.

Example 52 Synthesis of1-(4-(6-chloro-8-fluoro-7-(2-hydroxynaphthalen-1-yl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

1-(4-(6-Chloro-8-fluoro-7-(2-methoxynaphthalen-1-yl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

(2-Methoxynaphthalen-1-yl)boronic acid (904 mg, 98%, 5.88 eq.) andtetrakis (431 mg, 0.5 eq.) were added into a mixture of1-(4-(7-bromo-6-chloro-8-fluoroquinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one(297 mg, 1.0 eq.) in 1,4-dioxane (12 mL) and aqueous Na₂CO₃ (1M, 6 mL)in the sealed tube. The reaction mixture was heated at 120° C. in theMicrowave Reactor for 15 min. After cooling down, it was filtered. Thefiltrate was diluted with ethyl acetate, and washed with water. Theseparated organic layer was dried over Na₂SO₄, and concentrated invacuo. The residue was used directly in the next step.

1-(4-(6-Chloro-8-fluoro-7-(2-hydroxynaphthalen-1-yl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-one

To a solution of above obtained1-(4-(6-chloro-8-fluoro-7-(2-methoxynaphthalen-1-yl)quinazolin-4-yl)piperazin-1-yl)prop-2-en-1-onein dichloromethane (10 mL) at −78° C., BBr₃ in DCM (1M, 4.7 ml, 7 eq.)was added dropwise and the resulting mixture was stirred from −78° C. toroom temperature overnight. The reaction was quenched with saturatedaqueous NaHCO₃ solution at 0° C. The mixture was partitioned betweendichloromethane and water. The organic layer was dried with Na₂SO₄ andconcentrated in vacuo. The residue was purified by flash columnchromatography on silica gel (MeOH/DCM=1-10%) to afford the desiredproduct (100 mg, 29% yield in 2 steps) as a white solid. ¹H NMR (500MHz, DMSO-d6) δ: 9.98 (s, 1H), 8.71 (s, 1H), 8.9 (s, 1H), 7.95 (d, J=9Hz, 1H), 7.90 (d, J=9.0 Hz, 1H), 7.34 (m, 3H), 7.11 (d, J=8.0 Hz, 1H),6.84 (dd, J=17, 10.5 Hz, 1H), 6.18 (dd, J=17, 2.5 Hz, 1H), 6.18 (dd,J=10.5, 2.5 Hz, 1H), 3.96-3.79 (m, 8H). ESI-MS m/z: 463.1 [M+H]⁺.

Example 53 Biochemical Assay of the Compounds

Test compounds were prepared as 10 mM stock solutions in DMSO (Fishercat # BP-231-100). KRAS G12C 1-169, his-tagged protein, GDP-loaded wasdiluted to 2 μm in buffer (20 mM Hepes, 150 mM NaCl, 1 mM MgCl₂).Compounds were tested for activity as follows:

Compounds were diluted to 50× final test concentration in DMSO in96-well storage plates. Compound stock solutions were vortexed beforeuse and observed carefully for any sign of precipitation. Dilutions wereas follow:

-   -   For 100 μM final compound concentration, compounds were diluted        to 5000 μM (5 μl 10 mM compound stock+5 μl DMSO and mixed well        by pipetting.    -   For 30 μM final compound concentration, compounds were diluted        to 1500 μM (3 μl 10 mM compound stock+17 μl DMSO) and mixed well        by pipetting.    -   For 10 μM final compound concentration, compounds were diluted        to 500 μM (2 μl 10 mM compound stock+38 μl DMSO) and mixed well        by pipetting.        49 μl of the stock protein solution was added to each well of a        96-well PCR plate (Fisher cat #1423027). 1 μl of the diluted 50×        compounds were added to appropriate wells in the PCR plate using        12-channel pipettor. Reactions were mixed carefully and        thoroughly by pipetting up/down with a 200 μl multi-channel        pipettor. The plate was sealed well with aluminum plate seal,        and stored in drawer at room temperature for 30 min, 2 hour or        24 hrs. 51 μl of 2% formic acid (Fisher cat # A117) in DI H₂O        was then added to each well followed by mixing with a pipette.        The plate was then resealed with aluminum seal and stored on dry        ice until analyzed as described below.

The above described assays were analyzed by mass spectrometry accordingto the following procedure:

The MS instrument is set to positive polarity, 2 GHz resolution, and lowmass (1700) mode and allowed to equilibrate for 30 minutes. Theinstrument is then calibrated, switched to acquisition mode and theappropriate method loaded.

After another 30 minute equilibration time, a blank batch (i.e., buffer)is run to ensure equipment is operating properly. The samples are thawedat 37° C. for 10 minutes, briefly centrifuged, and transfer to the benchtop. Wells A1 and H12 are spiked with 1 uL 500 uM internal standardpeptide, and the plates centrifuged at 2000×g for 5 minutes. The methodis then run and masses of each individual well recorded.

The masses (for which integration data is desired) for each well arepasted into the platemap and exported from the analysis. Masses for theinternal standards are exported as well. The data at 50 ppm is extractedfor the +19 charge state, and identity of well A1 is assigned using theinternal standard spike and integrated. Peak data is exported as a TOFlist and the above steps are repeated individually, for the +20, 21, 22,23, 24, and 25 charge states.

Other in vitro analyses are as follows:

Inhibition of Cell Growth:

The ability of the subject compounds to inhibit RAS-mediated cell growthis assessed and demonstrated as follows. Cells expressing a wildtype ora mutant RAS are plated in white, clear bottom 96 well plates at adensity of 5,000 cells per well. Cells are allowed to attach for about 2hours after plating before a compound disclosed herein is added. Aftercertain hours (e.g., 24 hours, 48 hours, or 72 hours of cell growth),cell proliferation is determined by measuring total ATP content usingthe Cell Titer Glo reagent (Promega) according to manufacturer'sinstructions. Proliferation EC50s is determined by analyzing 8 pointcompound dose responses at half-log intervals decreasing from 100 μM.

Inhibition of RAS-Mediated Signaling Transduction:

The ability of the compounds disclosed herein in inhibiting RAS-mediatedsignaling is assessed and demonstrated as follows. Cells expressing wildtype or a mutant RAS (such as G12C, G12V, or G12A) are treated with orwithout (control cells) a subject compound. Inhibition of RAS signalingby one or more subject compounds is demonstrated by a decrease in thesteady-state level of phosphorylated MEK, and/or Raf binding in cellstreated with the one or more of the subject compounds as compared to thecontrol cells.

Inhibition of RAS-mediated signaling transduction:

The ability of the compounds disclosed herein in inhibiting RAS-mediatedsignaling is assessed and demonstrated as follows. Cells expressing wildtype or a mutant RAS (such as G12C, G12V, or G12A) are treated with orwithout (control cells) a subject compound. Inhibition of RAS signalingby one or more subject compounds is demonstrated by percentage bindingof compound to the G12C mutated RAS protein in cells treated with theone or more of the subject compounds as compared to the control cells.

Inhibition of RAS-Mediated Signaling Transduction:

The ability of the compounds disclosed herein in inhibiting RAS-mediatedsignaling is assessed and demonstrated as follows. Cells expressing wildtype or a mutant RAS (such as G12C, G12V, or G12A) are treated with orwithout (control cells) a subject compound. Inhibition of RAS signalingby one or more subject compounds is demonstrated by a decrease inbinding of RAS complex to downstream signaling molecules (for exampleRaf) in cells treated with the one or more of the subject compounds ascompared to the control cells.

Each of the compounds in Table 1 were tested according to the abovemethods and found to covalently bind to KRAS G12C to the extent of atleast about 5% (i.e., at least about 5% of the protein present in thewell was found to be covalently bound to test compound).

TABLE 2 Activity of Representative Compounds* Binding No. % No. Binding% No. Binding % No. Binding % 1 +++ 2 + 3 + 4 ++++ 5 +++ 6 +++ 7 ++++ 8++ 9 +++ 10 ++ 11 ++++ 12 + 13 ++ 14 ++ 15 +++ 16 ++ 17 + 18 ++ 19 ++20 + 21 +++ 22 + 23 ++ 24 + 25 ++ 26 ++ 27 ++ 28 + 29 + 30 + 31 + 32 +33 ++ 34 +++ 35 + 36 + 37 ++ 38 ++ 39 + 40 +++ 41 + 42 +++ 43 +++ 44 +++45 + 46 ++++ 47 ++++ 48 ++++ 49 ++++ 50 + 51 ++++ 52 ++++ 53 ++++ 54 ++55 ++++ 56 ++++ 57 + 58 +++ 59 ++++ 60 + 61 + 62 + 63 + 64 ++ 65 + 66++++ 67 +++ 68 + 69 + 70 +++ 71 + 72 ++ 73 ++ 74 +++ 75 + 76 + 77 +++78 + 79 + 80 + 81 +++ 82 + 83 ++ 84 ++ 85 +++ 86 + 87 + 88 + 89 + 90 +91 ++ 92 + 93 + 94 ++ 95 ++ 96 + 97 ++ 98 + 99 +++ 100 +++ 101 +++ 102+++ 103 ++ 104 +++ 105 + 106 ++++ 107 ++++ 108 ++ 109 ++++ 110 +++ 111+++ 112 +++ 113 +++ 114 +++ 115 +++ 116 ++ 117 +++ 118 +++ 119 +++ 120+++ 121 ++++ 122 ++ 123 ++++ 124 +++ 125 ++++ 126 ++++ 127 ++++ 128 +++129 + 130 + 131 + 132 +++ 133 ++ 134 ++ 135 + 136 ++ 137 + 138 ++++ 139++++ 140 +++ 141 + 142 + 143 +++ 144 + 145 ++++ 146 ++++ 147 ++ 148 +++149 + 150 ++++ 151 + 152 +++ 153 ++++ 154 ++ 155 ++ 156 ++ 157 + 158++++ 159 +++ 160 + 161 ++ 162 + 163 + 164 + 165 N/A 166 + 167 + 168 ++169 +++ 170 + 171 +++ 172 +++ 173 ++++ 174 ++ 175 +++ 176 +++ 177 +178 + 179 + 180 + 181 + 182 +++ 183 +++ 184 ++++ 185 ++ 186 +++ 187 +++188 +++ 189 ++ 190 + 191 +++ 192 ++ 193 ++ 194 ++++ 195 ++++ 196 ++++197 ++ 198 ++++ 199 N/A 200 ++ 201 +++ 202 +++ 203 ++++ 204 +++ 205 +206 +++ 207 ++++ 208 ++++ 209 ++++ 210 ++++ 211 + 212 ++++ 213 ++ 214 +215 ++ 216 + 217 +++ 218 +++ 219 + 220 +++ 221 ++ 222 +++ 223 + 224 +++225 ++ 226 + 227 ++++ 228 + 229 ++ 230 + 231 +++ 232 + 233 +++ 234 ++++235 +++ 236 +++ 237 ++++ 238 +++ 239 +++ 240 +++ 241 + 242 ++++ 243 ++++244 + 245 + 246 ++++ 247 +++ 248 N/A 249 + 250 ++ 251 ++++ 252 ++++ 253++++ 254 +++ 255 +++ 256 +++ 257 ++++ 258 ++ 259 +++ 260 ++ 261 + 262 +263 + 264 ++ 265 + 266 +++ 267 + 268 +++ 269 +++ 270 +++ 271 +++ 272++++ 273 ++++ 274 ++++ 275 ++ 276 + 277 + 278 ++ 279 +++ 280 +++ 281 ++282 +++ 283 ++ 284 ++++ 285 +++ 286 + 287 ++ 288 ++ 289 +++ 290 +++ 291++++ 292 + 293 ++++ 294 ++++ 295 + 296 + 297 + 298 ++ 299 + 300 ++ 301++ 302 +++ 303 ++ 304 ++ 305 ++ 306 ++ 307 ++ 308 +++ 309 +++ 310 ++++311 +++ 312 ++++ 313 +++ 314 ++++ 315 + 316 ++ 317 N/A 318 + 319 ++ 320++ 321 + 322 +++ 323 +++ 324 + 325 ++ 326 + 327 ++ 328 + 329 ++ 330 ++331 ++ 332 ++ 333 + 334 ++++ 335 ++++ 336 +++ 337 + 338 ++ 339 ++++ 340++++ 341 ++++ 342 ++++ 343 +++ 344 +++ 345 ++++ 346 ++++ 347 ++++ 348++++ 349 +++ 350 ++++ 351 ++++ 352 ++++ 353 ++++ 354 ++++ 355 ++++ 356+++ 357 ++++ 358 ++++ 359 ++++ 360 ++++ 361 ++++ 362 ++ 363 ++++ 364++++ 365 ++++ 366 ++++ 367 ++++ 368 ++++ 369 ++++ 370 + 371 ++ 372 +++373 +++ 374 +++ 375 +++ 376 N/A *Binding for compounds 1-47 was measuredat 24 h; binding for compounds 48-246 was measured at 2 h; binding forcompounds 247-375 was measured at 30 min. N/A = results pending +indicates binding activity from 5% to 25% ++ indicates binding activitygreater than 25% and up to 50% +++ indicates binding activity greaterthan 50% and up to 75% ++++ indicates binding activity greater than 75%

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon-patent publications referred to in this specification or theattached Application Data Sheet are incorporated herein by reference, intheir entirety to the extent not inconsistent with the presentdescription.

From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention. Accordingly, the invention is notlimited except as by the appended claims.

1-95. (canceled)
 96. A compound having the following structure (I′b):

or a pharmaceutically acceptable salt, tautomer, or stereoisomerthereof, wherein:

represents a double bond;

represents a double or triple bond; Q is —C(═O)—, —C(═NR^(8′))—,—NR⁸C(═O)—, —S(═O)₂— or —NR⁸S(═O)₂—; X is CR⁶; Y is N; Z is N; L¹ is abond; L² is a bond or alkylene; R′ is R¹ and R″ is R^(2c); or R′ is Hand R″ is R¹; R¹ is heterocyclyl, heteroaryl or aryl; R^(2a), R^(2b) andR^(2c) are each independently H, halo, —OH, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₃-C₈ cycloalkyl, heteroaryl or aryl; R^(3a)and R^(3b) are, at each occurrence, independently H, —OH, —NH₂, —CO₂H,halo, cyano, C₁-C₆ alkyl, C₂-C₆ alkynyl, hydroxyalkyl, aminylalkyl,alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl oraminylcarbonyl; R^(4a) and R^(4b) are, at each occurrence, independentlyH, —OH, —NH₂, —CO₂H, halo, cyano, C₁-C₆ alkyl, C₂-C₆ alkynyl,hydroxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl or aminylcarbonyl; R⁶ is H, cyano, cyanoalkyl,amino, aminylalkyl, aminylalkylaminyl, aminylcarbonyl, aminylsulfonyl,—CO₂NR^(a)R^(b), alkylaminyl, haloalkylaminyl, hydroxyalkylaminyl,amidinylalkyl, amidinylalkoxy, amidinylalkylaminyl, guanidinylalkyl,guanidinylalkoxy, guanidinylalkylaminyl, C₁-C₆ alkoxy, aminylalkoxy,alkylaminylalkoxy, alkylcarbonylaminylalkoxy, C₁-C₆ alkyl, heterocyclyl,heterocyclyloxy, heterocyclylalkyloxy, heterocyclylaminyl,heterocyclylalkylaminyl, heteroaryl, heteroaryloxy, heteroarylalkyloxy,heteroarylaminyl, heteroarylalkylaminyl, aryl, aryloxy, arylaminyl,arylalkylaminyl or arylalkyloxy; R^(a) and R^(b) are each independentlyH or C₁-C₆ alkyl; or R^(a) and R^(b) join to form a carbocyclic orheterocyclic ring; R⁸ is H, C₁-C₆ alkyl or hydroxyalkyl; R^(8′) is H,—OH, cyano or C₁-C₆ alkyl; when

is a double bond then R⁹ and R¹⁰ are each independently H, cyano,carboxy, C₁-C₆ alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl,heteroaryl or hydroxyalkyl or R⁹ and R¹⁰ join to form a carbocyclic orheterocyclic ring; and when

is a triple bond then R⁹ is absent and R¹⁰ is H, C₁-C₆ alkyl,aminylalkyl, alkylaminylalkyl or hydroxyalkyl, wherein each alkylene,heterocyclyl, heteroaryl, aryl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, alkoxycarbonyl, C₃-C₈ cycloalkyl, C₂-C₆ alkynyl, hydroxyalkyl,aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl,aminylcarbonylalkyl, aminylcarbonyl, aminylalkylaminyl, aminylcarbonyl,aminylsulfonyl, carbocyclic ring, heterocyclic ring, alkylaminyl,haloalkylaminyl, hydroxyalkylaminyl, amidinylalkyl, amidinylalkoxy,amidinylalkylaminyl, quanidinylalkyl, guanidinylalkoxy,guanidinylalkylaminyl, aminylalkoxy, alkylaminylalkoxy,alkylcarbonylaminylalkoxy, heterocyclyloxy, heterocyclylalkyloxy,heterocyclylaminyl, heterocyclylalkylaminyl, heteroaryloxy,heteroarylalkyloxy, heteroarylaminyl, heteroarylalkylaminyl, aryloxy,arylaminyl, arylalkylaminyl and arylalkyloxy is optionally substitutedwith one or more substituents selected from the group consisting ofaminyl, cyano, hydroxy, imino, nitro, oxo, thioxo, halo, aminylsulfonyl,aminylcarbonyl, C₁-C₁₂ alkyl, C₁-C₆ alkylaminylcarbonyl,aminylcarbonylC₁-C₆ alkyl, C₁-C₁₂ haloalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkoxyalkyl, C₁-C₆ haloalkoxyalkyl, cyanoC₁-C₆ alkyl,C₁-C₆ alkylcycloalkyl, C₁-C₆ alkylheterocycloalkyl, C₂-C₆ alkynyl, C₁-C₆alkylaminyl, C₁-C₆ alkylcarbonylaminyl, C₁-C₆ hydroxyalkyl, C₂-C₆alkenylcarbonylaminyl, C₁-C₆ thioalkyl, aryl, aralkyl, C₃-C₈ cycloalkyloptionally substituted with cyano, C₃-C₈ cycloalkylalkyl,aminylcarbonylC₃-C₈ cycloalkyl, C₃-C₈ cycloalkylaminylcarbonyl, C₃-C₈fused cycloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl,heteroaryl, N-heteroaryl and heteroarylalkyl.
 97. The compound of claim96, wherein the compound has the following structure (I′f):


98. The compound of claim 96, wherein the compound has the followingstructure (I′j):


99. The compound of claim 96, wherein R¹ is optionally substituted aryl.100. The compound of claim 99, wherein R¹ is optionally substitutedphenyl.
 101. The compound of claim 99, wherein R¹ is substituted withone or more substituents.
 102. The compound of claim 101, wherein thesubstituents are selected from the group consisting of halo, cyano,cyanoC₁-C₆ alkyl, cyanoC₃-C₈ cycloalkyl, hydroxy, C₁-C₆ alkyl, C₁-C₆alkylcycloalkyl, C₂-C₆ alkynyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆alkylaminyl, C₁-C₆ alkylcarbonylaminyl, C₁-C₆ hydroxyalkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxyalkyl, aminylsulfonyl, aminylcarbonyl,aminylcarbonylC₁-C₆ alkyl, aminylcarbonylC₃-C₈ cycloalkyl, C₁-C₆alkylaminylcarbonyl, C₃-C₈ cycloalkylaminylcarbonyl, C₃-C₈cycloalkylalkyl, C₃-C₈ cycloalkyl, C₃-C₈ fused cycloalkyl andheteroaryl.
 103. The compound of claim 102, wherein the substituents areselected from the group consisting of fluoro, chloro, bromo, cyano,hydroxy, hydroxymethyl, methoxy, methoxymethyl, methyl, ethyl,isopropyl, difluoromethyl, trifluoromethyl, aminylcarbonyl andcyclopropyl.
 104. The compound of claim 99, wherein R¹ has one of thefollowing structures:


105. The compound of claim 96, wherein R¹ is optionally substitutedheterocyclyl or optionally substituted heteroaryl.
 106. The compound ofclaim 105, wherein R¹ is optionally substituted: thiophenyl, pyridinyl,pyridinonyl, pyrimidinyl, benzooxazolyl, benzoisoxazolyl,benzodioxazolyl, benzoimidazolyl, quinolinyl, quinolinonyl,dihydroquinolinonyl, tetrahydroquinolinyl, quinazolinyl, indazolyl,indolinonyl, benzothiophenyl or dihydrobenzodioxinyl.
 107. The compoundof claim 105, wherein R¹ is substituted with one or more substituents.108. The compound of claim 107, wherein the substituents are selectedfrom the group consisting of halo, C₁-C₆ alkyl, C₁-C₆ alkoxy and C₂-C₆alkenylcarbonylaminyl.
 109. The compound of claim 107, wherein thesubstituents are selected from the group consisting of fluoro, chloro,amino and methyl.
 110. The compound of claim 105, wherein R¹ has one ofthe following structures:


111. The compound of claim 96, wherein R^(2a) is halo.
 112. The compoundof claim 111, wherein R^(2a) is chloro or fluoro.
 113. The compound ofclaim 96, wherein R^(2b) is halo.
 114. The compound of claim 113,wherein R^(2b) is chloro or fluoro.
 115. The compound of claim 96,wherein Q is —C(═O)—.
 116. The compound of claim 96, wherein at leastone of R⁹ or R¹⁰ is H.
 117. The compound of claim 116, wherein each ofR⁹ and R¹⁰ are H.
 118. The compound of claim 96, wherein

has one of the following structures:


119. The compound of claim 96, wherein

has the following structure:


120. The compound of claim 96, wherein L² is a bond.
 121. The compoundof claim 96, wherein R^(3a), R^(3b), R^(4a) and R^(4b) are each H. 122.The compound of claim 96, wherein R⁶ is H.
 123. The compound of claim96, wherein the compound has one of the following structures:


124. A pharmaceutical composition comprising a compound of claim 96 anda pharmaceutically acceptable carrier.